Oral appliance for delivery of medicaments and/or other substances

ABSTRACT

An oral appliance is provided for delivering a medicament to at least a portion of teeth and/or soft tissue areas inside a mouth. The oral appliance contains an interior surface having a medicament disposed in or on at least a portion of and/or the entire interior surface of the oral appliance. The interior surface of the oral cavity is formed to fit contours of at least the portion of the teeth and/or soft tissue areas inside the oral cavity and is configured for holding the medicament in contact with at least the portion of the teeth and/or soft tissue areas inside the oral cavity to deliver the medicament to strategic areas in need of treatment. In some embodiments, computer, network and computer readable storage media are provided.

BACKGROUND

Medicaments may be delivered to patients by a variety of ways includingoral, intravenous, intramuscular, inhalation, topical, patches, rectal,subcutaneous or local routes of administration to treat the target site.The method of delivery chosen depends, among other things, upon thecondition being treated, desired therapeutic concentration of themedicament and the duration of medicament concentration that must bemaintained at the target site.

Recently, there has been considerable interest in delivering medicamentsvia the oral cavity (e.g., gums, buccal, and sublingual areas, etc.).Delivery to target sites of the oral cavity has several advantages. Oneadvantage is that it allows localized treatment of the teeth, gums andother soft tissues. Another advantage is that the oral cavity has anextensive network of blood capillaries under the mucosa that isparticularly suited to provide rapid and effective systemic absorptionof systemic medicaments.

Delivery of medicaments to target sites in the oral cavity, unlike theintravenous (IV), intramuscular (IM), and subcutaneous (SC) routes, doesnot require sterilized hypodermic needles and does not raise concernsabout the safe disposal of needles and accidental needle sticks.

Many, if not most, patients experience anxiety and exhibit symptoms ofstress when faced with hypodermic injections via the IM, IV, or SCroutes. Burning, edema, swelling, turgidity, hardness and soreness atthe injection site can often occur.

Non-invasive topical delivery of medicaments to the oral cavity avoidsthese problems associated with injections. Non-invasive delivery ofmedicaments to the oral cavity also has the advantage of avoidingdigestive first pass metabolism, where enzymatic degradation within thegastrointestinal tract destroys certain medicaments when taken in pillform orally and administered per oral (PO). For example, therapeuticpeptides such as insulin, erythropoietin, and human growth hormone donot survive the acidic milieu of the stomach and cannot be administeredorally (PO).

Many oral medicaments are commercially available for cosmetic andtherapeutic use, which are delivered locally to the oral cavity. Thesemedicaments are formulated as mouthwashes, rinses, toothpastes, dentalgels, tooth powder, chewing gum, lozenges, strips and similar productsto treat a variety of conditions including preventing dental calculusformation, dental caries, periodontitis and gingivitis, tooth whitening,as well as the elimination of halitosis. While these formulationsprovide some benefits, they often require a higher dose, do not stay atthe target site long enough for adequate delivery of the medicament, canaffect non-targeted tissues leading to adverse side effects and arediluted away by saliva also decreasing effectiveness.

Oral appliances that allow non-invasive delivery of medicaments havebeen developed that have a reservoir to hold liquid medicaments to bedelivered. These oral appliances are available in universal sizes togenerically fit adults or are custom made for a precise fit to the teethand gums of the individual patient. To whiten teeth, these oralappliances are becoming increasingly popular as over-the-counter toothwhitening systems or as part of a treatment plan from dentalprofessionals.

Many oral appliances require the patient or dental professional to fillthe reservoir with the liquid medicament. This can be costly and timeconsuming, and can be very messy with bulky dispensers requiringdexterity particularly when the patient is filling the oral appliance byhimself/herself in the confines of their home. This leads to poorpatient compliance and the failure of the treatment itself. Often theliquid medicament held by the oral appliance undesirably leaks out ofthe oral appliance and contacts off target areas of the mouth causingunwanted treatment of these non-targeted areas often with deleteriousside effects such as burning, stinging and irritation and altered tastesensations. Sometimes medicament can leak out of the appliance and thepatient will swallow the medicament into the gastro-intestinal tract—nota desirable outcome. This loss of medicament may lead to reducedefficacy in the treatment.

Based on the above, new oral appliances are needed that improve deliveryof the medicament to the target site. Oral appliances that can be easilymanufactured, are preloaded and pre-dosed with medicaments, which reduceunwanted leakage, that are easy and comfortable for the patient and arenot limited to the confines of home or a bathroom are also needed.

SUMMARY

New oral appliances are provided that deliver medicaments and/or tissuesto an oral cavity in a three dimensional manner. In various embodimentsan oral appliance is provided for delivering a medicament to at least aportion of teeth and/or soft tissue areas inside a mouth. The oralappliance contains an interior surface having a medicament disposed inor on at least a portion of and/or the entire interior surface of theoral appliance. The interior surface of the oral cavity is formed to fitcontours of at least the portion of the teeth and/or soft tissue areasinside the oral cavity and is configured for supporting and holding themedicament in contact with at least the portion of the teeth and/or softtissue areas inside the oral cavity to deliver the medicament. Invarious embodiments, the oral appliance is monolithic or a single pieceand the interior surface custom fit and formed to fit contours of theteeth and/or soft tissue areas inside the oral cavity of a patient inneed of treatment. Unlike prior art devices, the device of the presentapplication has the medicament and/or cells as part of the device andthe medicament and/or cells are not removable from it. In certainembodiments, the oral appliance comprises, consists essentially of orconsists one, two, three, four, five or oral appliances.

In certain embodiments, the material of the oral appliance is a polymergel, a hydrogel, a brush polymer or a combination thereof. In someembodiments, the hydrogel comprises, consists essentially of or consistsof an amount from about 10% to about 90% by weight, from about 20% toabout 80% by weight, from about 30% to about 70% by weight, from about40% to about 60% by weight and the medicament comprises, consistsessentially of or consists of an amount from about 0.01% to about 50%,from about 0.1% to about 20% by weight, from about 0.5% to about 10%,from about 1% to about 7% by weight.

In some embodiments, the oral appliance is constructed from a digitaldata set representing at least a portion of or all of the teeth and/orsoft tissue areas inside the oral cavity.

In some embodiments, there is an oral appliance for delivering amedicament to at least a portion of teeth and/or soft tissue areasinside an oral cavity, the oral appliance comprising an interior surfacehaving a medicament disposed in or on at least a portion of and/or allof the interior surface of the oral appliance, the interior surfacebeing formed to fit contours of at least the portion of the teeth and/orsoft tissue areas inside the oral cavity and being configured forholding the medicament in contact with at least the portion of the teethand/or soft tissue areas inside the oral cavity to deliver themedicament thereto.

In some embodiments, there is a method of delivering a medicament to theteeth and soft tissues inside the oral cavity, the method comprising:providing an oral appliance comprising an interior surface having amedicament disposed in or on at least a portion of and/or all of theinterior surface of the oral appliance, the interior surface beingformed to fit contours of at least the portion of the teeth and/or softtissue areas inside the oral cavity and being configured for supportingand holding the medicament in contact with at least the portion of theteeth and/or soft tissue areas inside the oral cavity to deliver themedicament.

In some embodiments, there is a computer implemented method of making anoral appliance, the method comprising: creating a digital record of apatient's oral cavity which is called the Base Image (BI). The BI can beobtained by the conventional analog method of taking an impression ofthe patient's mouth with common impression materials such as alginate,polyvinyls, silicones or other such materials or may be taken withvarious scanning devises for a more direct digital record of thetopography of the patient's mouth. With the analog method either theimpression would be poured with dental stone and the positive modelwould be scanned or the impression itself, the negative, would bescanned yielding a digital record of the BI. From the Base Image, whichis a permanent record of the topography of the patient's mouth and wouldbe digitally stored for future iterations of appliances, computerizedprogram manipulations are made to create the first digital image (Dig1)of at least a portion of the teeth, and/or soft tissue of the oralcavity. Dig1 is an additive process in which programmatically theplatform appliance image is digitally layered over the Base Image (BI).Dig1 is the platform carrier for delivering medicaments and/or cells tothe mouth. A second subtractive process of the Base Image, BI, isprogrammatically made and this image is stored as the second digitalimage (Dig2). Dig2 is a three dimensional representation of thegeographic area to be targeted by the oral appliance. The second digitalimage (Dig2) is a subtractive process made through program manipulationsto treat at least a portion of the teeth and/or soft tissue of the oralcavity in need of treatment; combining the first digital image (Dig1)with the second digital image, Dig2, forms a final third digital image(Dig3) of the oral cavity with the treatment area. It is from this thirddigital image that the appliance is printed and made virtually throughthe computer.

In some embodiments, there is a computer system for making an oralappliance pre-loaded with at least one medicament or at least a tissuefor grafting, the computer system comprising additive logic encoded inthe computer for generating Dig1 data based upon at least a portion ofthe teeth and/or soft tissues areas of the oral cavity of a patient, theBase Image, data generated using an imaging device. Further logicencoded in the computer for generating Dig2 data by performing a digitalsegmentation of at least a portion of the teeth and/or soft tissuesareas of the oral cavity to determine discrete regions of the oralcavity in need of treatment, logic encoded in the computer for combiningthe Dig1 data and the Dig2 data to form the Dig3 data from which theoral appliance can be produced, wherein the Dig3 data comprisespositions for at least one medicament to be placed at the discreteregions in the oral cavity in need of treatment.

In some embodiments, there is a network based computer system for makingan oral appliance pre-loaded with at least one medicament or at least atissue for grafting, the network based computer system comprising logicencoded in the network for generating Dig1 data representing an additiveoverlay of at least a portion of the teeth and/or soft tissues areas ofthe oral cavity of a patient built upon the Base Image. The Base Image(BI) data generated using an imaging device, logic encoded in thenetwork for generating Dig2 data by performing a digital segmentation ofat least a portion of the teeth and/or soft tissues areas of the oralcavity to determine discrete regions of the oral cavity in need oftreatment, logic encoded in the network for combining the Dig1 data andthe Dig2 data to form the Dig3 data from which the oral appliance can beproduced, wherein the Dig3 data comprises positions for at least onemedicament to be placed at the discrete regions in the oral cavity inneed of treatment. Essentially the original image of the mouth (BI)provides the template for creating the additive first digital image(Dig1) and the segmented second digital image (Dig2) through variousprogram manipulations of the base image of the mouth (BI) to form afinal treatment third digital image of the mouth (Dig3) from which imagethe appliance will be fabricated.

In some embodiments, there is a computer readable storage medium storinginstructions that, when executed by a computer, cause the computer to:receive BI data from an imaging device, from which image an additivemanipulation is performed yielding the Dig1 data representing theplatform carrier over at least a portion of the teeth and/or softtissues areas of the oral cavity of a patient. The BI is then againmanipulated to generate a Dig2 data by performing a digital segmentationof at least a portion of the teeth and/or soft tissues areas of the oralcavity to determine discrete regions of the oral cavity in need oftreatment. A merging of the additive Dig1 data with the subtractive Dig2manipulation forms the Dig3 data from which the oral appliance can beproduced, wherein the Dig3 data comprises positions for at least onemedicament to be placed at the discrete regions in the oral cavity inneed of treatment.

In some embodiments, there is an oral appliance for collecting a samplefrom at least a portion of teeth and/or soft tissue areas inside an oralcavity, the oral appliance comprising an interior surface having anabsorptive material disposed in or on at least a portion of and/or allof the interior surface of the oral appliance, the interior surfacebeing formed to fit contours of at least the portion of the teeth and/orsoft tissue areas inside the oral cavity and being configured forholding the absorptive material in contact with at least the portion ofthe teeth and/or soft tissue areas inside the oral cavity to collect thesample therefrom. The absorptive material would follow the geographicareas of the mouth to be tested and would be a Dig2 manipulation of theBase Image.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates an enlarged side view of an embodiment of the oralappliance covering the teeth and/or soft tissues of a patient, the oralappliance without teeth and/or soft tissues inserted in the oralappliance.

FIG. 2 illustrates an enlarged side view of an embodiment of the oralappliance, where the medicament is shown as infused polymer gel layerthat is adjacent to the gingival sulcus region. This view has the teethand gums loaded in the interior surface of the oral appliance and theoral appliance can be transparent or non-transparent.

FIG. 3 illustrates a cross section of an embodiment of an oral applianceas a dental oral appliance having the medicament in a hydrogel layer.

FIG. 4 illustrates an enlarged side cross sectional view of anembodiment of the oral appliance configured to correspond to and coverthe tooth and soft tissue areas inside the oral cavity. The interiorsurface encompasses the polymer gel material having the medicament.

FIG. 5 illustrates an embodiment of a virtual image (Dig2) of theregions along the sulcus (gumline) where the medicament of the oralappliance will be loaded in a polymer gel material. The medicament isdisposed at discrete or continuous regions throughout the polymer gelmaterial and corresponds to the regions that will require treatment.FIG. 5 is a representation of segmenting out the gumline from the BaseImage.

FIG. 5A illustrates an enlarged view of a virtual image (Dig2) of theregions along the sulcus (gumline) where the medicament of the oralappliance will be loaded in a polymer gel material.

FIG. 5B illustrates an enlarged interior view of a virtual image (Dig1)of the oral appliance that is made by taking the Base Image (BI) of theoral cavity and creating a digital image that additively layers over theoral cavity including the teeth, gums, soft tissue areas and/or thepalate. Dig1 does not have the virtual image of where the medicament isto be disposed.

FIG. 5C illustrates an enlarged interior view of a virtual image (Dig3)of the oral appliance. The virtual image is the merging of the additiveDig1 data and the subtractive data of Dig2 from, which the oralappliance can be produced that has regions along the sulcus (gumline)where the medicament of the oral appliance will be loaded in a polymergel material.

FIG. 6 illustrates an embodiment of the computer-implemented system forproducing a pre-loaded oral appliance.

FIG. 7 is a flow chart illustrating an embodiment of thecomputer-implemented system for producing a pre-loaded oral appliance.

FIG. 8 is a flow chart illustrating an embodiment of thecomputer-implemented system to generate and manufacture an oralappliance and its use by a prospective patient.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a medicament” includes one, two, three or moremedicaments.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents, which may be included within the invention as defined bythe appended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

Oral Appliance

New oral appliances are provided that can deliver medicaments and/ortissues to at least a portion of the teeth and/or soft tissues insidethe oral cavity in a three dimensional way. One advantage of the oralappliance is that it is custom made to fit only one patient. As usedherein a “custom fit” oral appliance refers to an oral applianceprepared to correspond to at least a portion of the teeth or all of theteeth and soft tissues of a specific patient. Typically, the custom fitappliance is prepared by a dental care professional (e.g., dentist, oralsurgeon, medical doctor, other health care professional, manufacturer,etc.). The custom fit oral appliance can be made from an impressionmold, or using an analog or digital image capturing device. The oralappliance provided by this disclosure is not a boil and biteprefabricated device or a stock oral appliance, which can be manipulatedby the patient himself/herself with fingers to shape it against theteeth and gums. As opposed to other oral appliances available in theprior art, the appliances provided herein do not contain medicamentseparately in a cargo area or sponge or placed as a liquid in the oralappliance. The oral appliances disclosed herein are custom fit,disposable, monolithic devices, manufactured in one continuous step,pre-loaded with medicament in or on at least a portion of the interiorand/or exterior surfaces of the appliance and can deliver medicaments orgraft tissues three dimensionally. In some embodiments, the oralappliance can be transparent. Still another advantage of the oralappliance is that, in various embodiments, it can be easily manufacturedand is comfortable for the patient to use. Other advantages of the oralappliances provided by this disclosure include greater efficacy overconventional oral therapies based on two dimensional systems, userconvenience, enhanced patient compliance, lower dosage requirements,less dilution of medicament and enhanced applied pressure to gums.

In one embodiment, there is an oral appliance for delivering amedicament to at least a portion of teeth and/or soft tissue areasinside an oral cavity, the oral appliance comprising an interior surfacehaving a medicament disposed in or on at least a portion of and/or allof the interior surface of the oral appliance, the interior surfacebeing formed to fit contours of at least the portion of the teeth and/orsoft tissue areas inside the oral cavity and being configured forholding the medicament in contact with at least the portion of the teethand/or soft tissue areas inside the oral cavity to deliver themedicament thereto.

The soft tissue of the inside of the mouth, includes but is not limitedto any soft tissue adjacent or between the teeth, including but notlimited to the papilla, tissue of the upper and lower dental arches,marginal gingiva, gingival sulcus, inter-dental gingiva, gingival gumstructure on lingual and buccal surfaces up to and including themuco-gingival junction and/or the upper palate and/or the floor of themouth. In various embodiments, the soft tissue area includes themuco-buccal folds, hard and soft palates, lining mucosa, the tongueand/or attached gingival tissue. In various embodiments, the oralappliance receives one or more teeth including one or more molars,premolars, incisors, cuspids, tooth implant, or combination or portionsthereof. In other embodiments, the medicament contained in the oralappliance can be disposed anywhere in or on the interior or exteriorsurface of the oral appliance adjacent to the gum and/or other softtissue areas of the oral cavity including the front, back, occlusalsurfaces of one or more teeth.

Referring to FIG. 1, an enlarged side view of an embodiment of the oralappliance 10 is illustrated, which has an interior surface 12 andexterior surface 14, both comprising a polymer that can in someembodiments be in gel or hydrogel form. The interior surface 12 contactsone or more teeth and/or soft tissue areas of a patient. The interiorsurface 12 is custom fit to the individual patient's mouth andconfigured to receive all or a portion of the teeth and/or soft tissueareas inside the mouth. In this view the interior surface contacts theteeth and soft tissue. Oral appliances include, but are not limited to,oral trays, oral holders, oral covers, or the like that are designed tobe placed within the oral cavity. The interior surface 12 and/orexterior surface 14 of the oral appliance contain a medicament disposedin or on the polymer and the medicament can be disposed anywhere withinor on the oral appliance as part of a monolithic device. For example,the medicament can be disposed at discrete positions adjacent to thetreatment area or uniformly disposed throughout the device. As theinterior and/or exterior surface of the oral appliance contacts the oralcavity the medicament is released from the polymer (e.g., gel orhydrogel) by all or parts of the oral appliance contacting the desiredtreatment site or pressure from the device contacting tissue or fluid atthe treatment site (e.g., gums, tissue, teeth, etc.). In someembodiments, all or parts of the oral appliance can degrade over time bythe action of enzymes, by hydrolytic action and/or by other similarmechanisms in the oral cavity. In various embodiments, the degradationcan occur either at the surface of the oral appliance at discretepositions (heterogeneous or surface erosion) or uniformly throughout theoral appliance (homogeneous or bulk erosion). In some embodiments, allor discrete portions of the interior surface will degrade and releasemedicament at or near the target site in the oral cavity. The oralappliance will cover at least a portion of the teeth and or gums, byapplying the device over axis 8 to cover the area of the teeth and orgums and the oral appliance will be adjacent to the gingival sulcus 20,which will allow the medicament, if desired, to be released from thepolymer to this area.

Unlike orthodontic appliances, the present oral appliance is notdesigned to move teeth. Therefore, a plurality of oral appliances willbe configured to hold the teeth in the same position within theappliance. The teeth position will not change. However, the medicamentdisposed in or on the oral appliance will be in the same or differentareas at different stages of the treatment regimen with a variety oforal appliances. Thus, kits containing a plurality of devices can beprovided with different treatment stages.

FIG. 2 is an enlarged side view of an embodiment of an oral appliance.In this embodiment, the oral appliance is transparent and holds teeth 16and or gums, which are covered by it. The oral appliance comprises asurface that contains medicament as part of the polymer that in usereleases the medicament at or near the gingival sulcus 20.

FIG. 3 illustrates an enlarged cross sectional view of the portion ofthe oral appliance 30 and its contact points surrounding a tooth 32 andan interior surface 34 having at least a medicament infused polymer gellayer 36 which extends up and contacts the gingival sulcus region 38.The oral appliance is one piece and does not have the medicamentinserted into it. It will be understood that the medicament can bedisposed throughout the interior and/or exterior of the device thatcontacts oral tissue. In the embodiment shown in FIG. 3, the interior ofthe device has one or more medicaments disposed at discrete regions ofthe interior surface of the device adjacent to the areas to be treatedwith the medicament (e.g., tooth and/or soft tissue areas).

FIG. 4 illustrates an enlarged side cross sectional view of anembodiment of the oral appliance 40 showing an outline of a tooth 42.The oral appliance 40 has an exterior surface 44 and interior surface46. The interior surface of oral appliance 40 contains a medicamentinfused polymer gel or hydrogel, which contacts tooth 42 up to gingivalarea 48. In the embodiment shown, the medicament in the polymer layerextends and contacts the buccal surfaces of the teeth and surroundinggingival tissue and over adjacent gingival tissue on a lingual side ofthe teeth. In some embodiments, the oral appliance extends over occlusalsurfaces of the teeth and/or over lingual surfaces of the teeth in needof treatment.

In various embodiments, oral appliances disclosed herein can bemanufactured as more particularly described below. Generally, apatient's mouth is first scanned utilizing a digital data acquisitiontool. The data obtained in this manner can be used to form an initialdigital record, the Base Image (BT) and that image is retained in adatabase. A dental professional can also obtain an initial record of thepatient's oral cavity by taking an analog impression using alginate orother impression materials from which the analog model or impressionwill be scanned thus yielding the same BI. It is from this initialrecord of the patient's mouth, the Base Image (BI) that future oralappliances can be made. This image can be used as a permanent record ofthe patient's mouth which can then be digitally manipulated yielding athree dimensional representation of the tissues to be treated throughthe platform carrier, Dig1, and for various treatment modalities, Dig2.A virtual or real oral appliance, Dig3 is thereby formed by merging theadditive digital image, Dig1, with the segmentally manipulated image,Dig2, to create the final treatment image, Dig3. The Dig1 image mergedwith the Dig2 image creates the Dig3 image from which the oral appliancecan be created.

The Base Image provides an outline of at least a portion of and/or allthe surfaces of the teeth, gingiva and/or other soft tissues, which adental practitioner may wish to treat. Other soft tissues of the oralcavity include without limitations, the palate, muco-buccal andmuco-labial tissues, floor of the mouth, tongue, buccal and labialmucosae, and any other oral tissues. An authorized user can generateDig1 by using software to create a layer over the teeth and gingivawhich tightly approximate these tissues. The original image is nowdigitally enhanced to have a layer over it. Digital image Dig1 resemblesa virtual oral appliance, which can be used to create a real oralappliance. Dig1 is the platform carrier from which all future applianceswill be based. With respect to Dig1, the Base Image of the patient'steeth and gums has not been manipulated or modified by the computer atthis point, but has had a digitally represented overlay of teeth andsoft tissues. The additive process can be varied such that the platformcarrier (e.g., oral appliance) can be made thicker in some areas forstiffness and retention, such as over the teeth and thinner in otherareas for flexibility and comfort such as over the soft tissues. Theplatform carrier can also vary chemically in different regions such thatit may have a chemically stiffer polymer in one region and a moreflexible one in another region. Or the edge of the platform carrier canhave a swellable hydrogel to press against the soft tissues and therebylock in the medications and lock out the saliva thus preventing leakageout and leakage in. Other chemical or elastic formulations andpermutations thereof can be mixed and matched to suit a desired result.The current analog model of manufacturing may not yield thesevariations.

In some embodiments, Dig1 comprises the virtual image of portions of theoral appliance. By using virtual 3D imaging and 3D printing, one canutilize a gradient of physical and chemical characteristics to modifythe oral appliance itself. The printer can make portions of the oralappliance thicker for stiffness or thinner for flexibility and comfort.This is programmable in the computer system. In some embodiments, theoral appliance can modulate to give stiff or flexible variations whilekeeping the oral appliance at a uniform thickness.

The digital image is stored in the computer readable data storage mediaof the computer. Computer readable media, for example, store data thatis accessible by a computer, such as magnetic cassettes, flash memorycards, digital video disks, Bernoulli cartridges, random access memories(RAMs), read only memories (ROMs) or the like and may also be used inthe exemplary operating environment. Computer readable media does notinclude signals.

Using computer software, an authorized user can next generate a seconddigital image referred to as Dig2. The software generating Dig2 includespoints or discrete regions on the teeth and/or gingiva as boundariescorresponding to areas in the oral cavity that the dental practitionermay wish to treat. As used herein the “gingival margin area” comprisesan area within the oral cavity, which includes the gum line and theattached gingiva, including the sulcus of the gums. The gingival marginarea comprises about 2 to 3 mm of tooth above the gum line. In someembodiments, the points or the discrete regions may include buccalsurfaces of the teeth, surrounding gingival tissue, occlusal surfaces ofthe teeth, lingual surfaces of the teeth, and/or adjacent gingivaltissue on a lingual side of the teeth. Through software manipulation ofthe image of a patient's mouth, Dig2 can be subtracted according topoint boundaries to a predetermined depth which corresponds to thedesired thickness of the layer to be merged with Dig1. For example, insome embodiments, Dig2 can have a thickness layer of about 0.5 mm. Theresulting Dig2 image would be as if the dental professional took ascalpel blade and precisely removed the gums or gum line to a depth of0.5 mm and/or cut the teeth to a depth of 0.5 mm in one piece. This is asubtractive programming of virtual tissue, the slice of which is thenmerged precisely onto Dig1 in the exact area from which it was virtuallyremoved. It is digital image Dig2, which holds the medicaments requiredto treat a selected pathology.

FIG. 5 illustrates a virtual image of the polymer containing themedicament for the oral appliance. This illustrates the subtractiveprogramming. In this case the virtual 3D image 50 can be made byinputting data into the computer as to where the medicament is to bedisposed adjacent to the treatment areas of the oral appliance. Thecomputer system can generate the interior surface 52 of the device wheremedicament will be disposed in the polymer and be adjacent to thetreatment area. The 3D image can be generated by subtracting from theBase Image (BI) the soft and/or hard tissues to be treated in a precisepattern, yielding an image of the targeted area, Dig2, to be merged withthe original Dig1 platform device image. In some embodiments, thevirtual 3D image 50 of the oral appliance will not have a floor to it55. This is because, in some embodiments, the 3D image generated willonly have the discrete regions where the medicament is to be disposed(Dig2). The remainder of the virtual image of the device can beconstructed using a spatial geometric pattern 54 that can be used to addthe virtual 3D image of the floor of the oral appliance and the exteriorsurface of the oral appliance. This includes height, width and depth tothe virtual image. By utilizing the Dig2 software, a treatment systemcan be created in which medicaments can be delivered to targeted teethand/or tissues in a precise three dimensional manner. To date, previoussystems for delivering medicaments to the oral cavity have been twodimensional. For example rinses, pastes and lotions, delivered witheither a finger, an applicator, toothbrushes, trays or other oralappliance systems, either pre-loaded or patient loaded with medicaments,all wash or coat the teeth and/or tissues vertically and laterally. Byadding the dimension of depth to the vertical and lateral dimension, anoral appliance modeled upon Dig2 can deliver medicaments also in a thirddimension. The above Dig2 image is a precise subtraction of the targetedtissue accomplished through computer programming, which is then saved tobe used as further described below.

Once digital image Dig1 and digital image Dig2 have been generated, theycan be merged via computer modeling to generate a third and finaldigital image, Dig3. In this manner, a virtual platform carrier oralappliance (Dig1) generated on the BI can be combined with a virtualdigital image of the treatment area generated based on Dig2 such thatthe Dig2 image is precisely merged onto the Dig1 platform appliance onthe inside of the Dig1 oral appliance to correspond to the exact areafrom which it was removed. As a result, through an additive process Dig1can be merged with a subtractive process Dig2 to create a final computerenhanced image Dig3 which is a unique virtual three dimensional image ofthe oral appliance containing all or a portion of the oral appliancethat contains medicament in the areas adjacent to the treatment areas ofthe oral cavity that are unique to a given patient.

In some embodiments, it is contemplated that only the surfaces of theteeth will be treated and not the gums or only the gums will be treated.Teeth bleaching and caries prevention are examples of such processes.

Generating oral appliances that can provide a three dimensionaltreatment can be used effectively for providing different therapies formany pathologies of the oral cavity. In other embodiments, a bulge canbe placed on the exterior surface of the oral appliance, which wouldcorrespond to the lower jaw and the lingual aspect, which faces thefloor of the mouth and the lingual veins. In this process Dig1 isobtained as before, however Dig2 would be created through the additiveprocess of creating a bulge upon the exterior surface of Dig1. The bulgegenerated with Dig2 can hold medicaments to be absorbed directly intothe blood stream via the vasculature of the floor of the mouth,specifically the lingual veins by extending out from the tray under thetongue and pushing against the lingual veins. Based on the directabsorptive properties to the blood stream, oral appliances having anexternal surface having a bulge can be useful in delivering systemicdrugs to the body to treat many other diseases.

In another aspect, a virtual oral appliance Dig3 can be generated, whichcan be used by a dental professional to treat halitosis. The tongue hasa rough surface due to the papillae on the tongue. This roughnesscreates millions of tiny spaces among the papillae which harbormicroorganisms which frequently cause halitosis. In this aspect, thepalate cover and the palatal aspects of the upper jaw form the externalsurface of the Dig1 virtual oral appliance. As a result, the Dig2virtual oral appliance can be generated by adding a roughened surface,Velcro like in texture, which would include medicaments to treat thevolatile sulfur compounds produced by the microorganisms harbored amongpapillae and which cause halitosis. A virtual Dig3 oral appliancegenerated based on the resulting merger of Dig1 and Dig2 can be used asa scouring pad to treat halitosis. By closing the mouth and rubbing thetongue against the palate and the teeth, a patient could physicallycleanse the tongue in a scraping and/or rubbing motion. The rough,scouring pad surface of Dig3 covering the upper jaw and palate (roof ofmouth) can physically open and scrub the tiny spaces between papillaethereby allowing the simultaneous introduction of medicaments to killgerms and freshen the breath. This approach provides a differentsolution from scraping the tongue with a blade, a technique currentlyused by dental professionals to clean the tongue physically and aprocess which usually elicits a gag reflex or by the patient usingvarious tongue scraping devices to try to cleanse their tongue usuallyalso eliciting the gag reflex. When one closes their mouth and rubstheir tongue against the roof of their mouth there is no gag reflex,thus when rubbing the tongue to the palate with the above described oralappliance one will physically and chemically cleanse their mouth ofmalodor according to the Dig3 appliance.

FIG. 5A illustrates an enlarged view of a virtual image (Dig2) of theregions along the sulcus (gumline) 56 where the medicament of the oralappliance will be loaded in a polymer gel material.

FIG. 5B illustrates an enlarged view of a virtual image (Dig1) of theoral appliance 59 that is made by taking a baseline digital image of theoral cavity and creating a digital image that corresponds to or layersover the oral cavity including the teeth, gums, soft tissue areas and/orthe palate. Dig1 does not have the virtual image of where the medicamentis to be disposed. The lower portion 58 of the virtual oral appliancecorresponds to and will contact portions of the tongue and hard palate58 as well as the soft palate.

FIG. 5C illustrates an enlarged view of a virtual image (Dig3) of theoral appliance. The virtual image is the merging of the additive Dig1data and the subtractive data of Dig2 from, which the oral appliance canbe produced that has regions along the sulcus (gumline) 63 where themedicament of the oral appliance will be loaded in a polymer gelmaterial. The lower portion of the virtual oral appliance corresponds toand will contact portions of the tongue and hard palate as well as thesoft palate 65 and 67 along each side of the oral cavity. It is from Dig3 that the oral appliance can be manufactured.

In another embodiment, oral fungal infections can be treated, using thesame textured, palatal “scouring pad” (shown as 67 in FIG. 5C) oralappliance that can be generated based on a virtual Dig3 oral applianceobtained as discussed above with respect to halitosis. Fungal infectionsare often difficult to treat and eliminate. Historically, dentalprofessionals have used antifungal rinses or lozenges to treat fungalinfections. A patient afflicted with fungal infections would usuallyrinse for about a minute and/or suck on a lozenge for a couple ofminutes. By utilizing an oral appliance manufactured based on an virtualDig3 oral appliance, the tongue of a patient can be treated in part aswith halitosis, through rubbing and medicating with anti-fungalmedications, while the remaining portion of the oral appliance bothinterior and exterior aspects of which can be used to deliver the sameanti-fungal medications to virtually every surface of the oral cavity ina long and sustained manner which is essential in treating fungalinfections. In this embodiment, Dig2 can subtractively create a layerfor the entire inside of the oral appliance and additively add a layerto the non-palatal portion of the upper oral appliance and the entireouter portion of the lower oral appliance. Both upper and lower oralappliances can deliver medicaments to the entire mouth inside and out.Held by the teeth and gum, the upper and lower oral appliances canrelease medicaments through passive contact directly to the tissues.When one closes their mouth there is no open space since the softtissues collapse against each other and the hard tissues, such that theupper and lower appliances will contact all the tissues in a sustainedmanner. As a result, multiple rinsing and/or use of lozenges required byconventional therapies can be avoided. The fatigue factor frequentlyassociated with rinsing or sucking on lozenges is also avoided.

The methods described herein of developing oral appliances for threedimensional treatment can also find use in many surgical applications.In some embodiments, the boney defect of a cleft palate can be closed byproviding graft tissues utilizing the oral appliances of thisdisclosure. In cleft palates, there is a hole in the bone allowingcommunication between the mouth and the nose and sinuses. To allow fornormal chewing and swallowing, the cleft palate hole must be closed.Initially, a 3-D image of the defect is obtained by digital dataacquisition tools, such as X-ray devices, CAT scanners, MRI scanners,coordinate measuring machines, destructive scanners, ultra soundscanners and the like to capture or generate the Base Image.Subsequently, all the soft tissues lining the hole and the adjacentwalls of the bone which are thin and defective can be subtracted throughsubtractive computer manipulations. After subtracting the soft tissue,the desirable boney contours can be generated in a three dimensionalmanner following the topographical contours of the bone. The resultingdigital image (Dig2) for this application can be the entire piece ofbone that would be needed to “plug” the hole and fill the cleft palate.As described above, Dig2 can be added to Dig1 to generate a virtualdigital image 3 (Dig3) oral appliance. The Dig3 oral appliance caninclude an irregular shape rising out of its inside and attached to it.In this aspect, the Dig2 portion can be loaded with either live bonetissue or some synthetic bone. In other embodiments, the Dig2 imagecould be loaded with various layers of live tissue suspended medium tomaintain the live tissue and allow the tissue to grow (e.g., water,saline, dextrose, etc.).

In the cleft palate example discussed above, the oral appliance canprovide effective treatment in a three dimensional way. In thisembodiment, the virtual image of the cleft having a hole (Dig1) can befilled with a virtual image of the plug (Dig2) and the plug isconfigured to be received by the hole in the oral appliance adjacent tothe cleft palate. The Dig3 image will be a combination of Dig1 and Dig2and then the Dig3 image can be stored on the computer and then theinstructions for manufacturing the oral appliance and/or plug can besent to a 3D printing device.

The 3D printing can be accomplished using multiple print heads of astereolithography machine (e.g., for example 1, 2, 3, 4 or more printerheads can be available). The first three heads would print the Dig2portion such that print head 1 can print the sinus tissue or nasaltissue at the base of the oral appliance (e.g., top of the plug), printhead 2 which can print the bone in the body of the oral appliance (e.g.,body of plug), print head 3 can print the gingiva at the top of the plugand print head 4 would print Dig1 portion (platform carrier) thuscompleting the Dig3 protocol. To complete the surgical protocol, asecond Dig3 can be generated which has the same size and shape as thefirst Dig3. The resulting Dig3 appliance can be marked at the base witha dye to help the surgeon identify the area of soft tissue that needs tobe removed to get to the layer of bone to be treated, basically asurgical guide stent. Once marked, the surgeon could simply cut alongthe outline and remove the soft tissue. The oral appliance with the livetissue could then be precisely inserted into the mouth and heldprecisely in place according to the Dig1 image of the teeth. The Dig3oral appliance could either remain in place or be tacked down withstaples or sutures to keep it in place for the entire healing perioddesired. Once sufficient healing has occurred, the Dig1 portion of theappliance can be removed separating it from, in this case, the gingivaltissue at the interface of Dig2 subtracted from Dig1. The cleft palategraft derived in this manner will remain in place.

In other aspects, tooth loss, gingival and bone grafting procedures,implants, placement of regenerative tooth processes can also beaddressed by the methods described in this disclosure. In various otheraspects, the three dimensional methods described in this disclosure canbe useful to treat other diseases or surgical procedures of the body asa whole.

In some embodiments of the applications described above, once the Dig3virtual oral appliance is generated in whatever iteration, a virtual 3Dimage is sent to a stereolithography machine with at least two printheads to print or otherwise manufacture a treatment oral appliance. Oneprint head of the stereolithography machine can print the Dig1 portionof Dig3 and the other can print the Dig2 portion of Dig3 simultaneously.Thus, in one step, an entire oral appliance can be monolithicallymanufactured according to the instruction provided by Dig3. In variousembodiments, the print heads can use different chemical compositions.For example, in certain embodiments, the chemical composition for Dig1portion can be stiffer in order to better hold onto the teeth and gumsand be devoid of absorptive qualities while the Dig2 portion can be madeof a different chemical composition which has absorptive qualities andcan swell more easily. Useful chemical compositions comprise gels,hydrogels, polymer brushes and other swellable chemicals. These can bemixed uniformly with medicament, or alternately infused into Dig2material after printing of Dig3.

Stereolithography printing allows the two different chemicalcompositions of Dig1 and Dig2 to combine simultaneously into onemanufactured oral appliance, Dig3, without the use of adhesives ormechanical bonding. This is possible because the chemistry to allow thewedding of Dig1 and Dig2 has been worked out prior the manufacture andprinting of Dig3. Additionally, since the hydrogel or other chemicalused as a matrix for Dig2 is already loaded with the desiredmedicaments, the entire Dig3 oral appliance can be manufactured in onlyone sequence. There will be no soaks, dips, baths, sprays, or medicamentrinses to load the appliance.

In some embodiments, the computer program uses an axis graph withphysical properties on one axis and chemical properties on the other.These data are sent to print heads for manufacturing the device. Thedifferent print heads though holding different formulations will havechemical compatibility between them such that when printedsimultaneously the formulations will seamlessly meld together as onepiece thus allowing the Dig3 oral appliance to be fabricated at one timewithout the use of adhesives, glues or mechanical locking devises. Insome embodiments, the medicament can be loaded and printed concurrentlywith the overall oral appliance.

With this digital model the oral appliance manufactured in accordancewith Dig 3 is now ready to be placed in the oral cavity of the patienteither in a wet or dry form. The hydrogel portion of the Dig3 oralappliance will expand if dry when wetted or can be already expanded ifwet. In either case, the Dig2 portion of Dig3, which is the threedimensional representation of the area to be treated will release itsmedicaments to the affected area in a three dimensional manner once theoral appliance is inserted. For embodiments, where the one or morepolymers used to make the oral appliance comprises a hydrogel, thehydrogel of the Dig3 oral appliance will continuously diffuse out themedicaments along a diffusion gradient until the medicament is all orsubstantially all released. This phenomenon is similar to a biologic“wicking” caused by the body tissues of the patient, which will alwaysbe at a lower diffusion gradient since the tissues will constantly beabsorbing the medicaments thus being at the lower end of the diffusiongradient as the tissue absorbs the drug, it may be delivered to theblood stream. In some embodiments, for example, in bleachingmedicaments, the medicament will not to any significant extent bedelivered to the blood stream as the target tissue area is the teeth.

In various embodiments, the three dimensional model manufactured bystereolithography has the hydrogel loaded for pre-printing with themedicaments either in a liquid form or dried form (e.g., lyophilized)and the medicament can include salts, enantiomers, esters, epimers, orcombinations thereof. In the dried form, in some embodiments, themedicaments can become activated when wetted either with a liquid (e.g.,saline, water, saliva, blood or other bodily fluid) and then themedicament begins to diffuse out after the oral appliance is applied tothe oral cavity.

Once the oral appliances are printed or manufactured by astereolithography machine, the oral appliances are dried, packed andshipped to a dental professional who will deliver them to the patientwith instructions for their use. The patient then performs a single usetreatment and thereafter, after treatment, disposes of the oralappliance. A new tray is used for each treatment according to aprescribed regimen.

In some embodiments, oral appliances manufactured according to the threedimensional model described herein can also be utilized to treatperiodontal or gum diseases. In gum disease the initial form of the gumsis often reddened and swollen. As such, the gums are larger than normal.As they heal, the gums shrink back to their normal, healed state sizeand become pink and firm. In order to generate a Dig2 system to treatgum diseases, Dig2 can be modified to take into account the anticipatedshrinking of the gums to insure that the medicament layer is always inapposition to the diseased tissue. In some embodiments, if the gums areswollen by 2 mm, there can be a two week or 14 oral appliance treatmentperiod. The first oral appliance for use on the first day can have aninitial Dig2 thickness of 0.6 mm identified as Dig2A. The second oralappliance, identified as Dig2B, can have a thickness of 0.7 mm and canbe used by the patient on the second day. On the third day, the patientcan use Dig2C oral appliance, which can have a thickness of 0.8 mm. Theprocess repeats itself until day 14 when the thickness of Dig2N can be 2mm, thus fully accounting for the shrinkage of the gums and alsoallowing the medicaments to be always in direct contact with the gums.If this approach were not followed, the patient could end up with asituation where there would either be a gap between Dig2 and the gums orthe gums would not shrink completely. This is a progressive system inwhich the Dig3 oral appliances are manufactured to account for dailyand/or weekly changes to the desired therapy. Thus, in certainembodiments, the thickness of surface oral appliance is incrementallyconfigured for treatment of a gum disease. Such a precise approach couldnot be accomplished with analog devices used in a conventional twodimensional system.

The thickness of the Dig2 oral appliances can also be predicated by theswellable properties of the hydrogel. In some bleaching embodiments, theprescribed treatment would have the carbamide peroxide contact only theteeth and not the soft tissue of the oral cavity. In some embodiments,if nonswellable hydrogel is used, then Dig2 can subtract from the entiretooth surface about 0.2 mm including from buccal-labial,incisal-occlusal and lingual-palatal. This method would allow thebleaching of the entire tooth surface and not just the outsidebuccal-labial surface viewed when one smiles and which is the approachvirtually all other bleaching systems on the market use today. In yetother embodiments, if a hydrogel is formulated at 50% expansion, thenthe Dig2 subtraction image would be 50% less to allow for the expansionof the hydrogel to cover the entire tooth. Dig2 could still be 0.2 mmthick but the surface areas of the teeth that are subtracted could beless by 50%. Thus, the physical expansion of the chemical compositionsutilized in the oral appliances described herein and the resultingdimensional changes can be manipulated by computer software in a precisescientific manner. For example, to allow further for the swellableproperties of hydrogel, the software program can employ a spatialgeometric pattern system. In this example, the Dig2 image could print ina geometric or random pattern that accounts for the predeterminedexpansion of the medicament infused hydrogel. As a result, Dig3, thesoftware program for printing can also take into account the expansionfactors of hydrogel when directing the print head to print.

In other embodiments, the swelling properties of the hydrogel can bevaried. Multiple print heads of a stereolithography machine can containdifferent formulations of medicament containing hydrogel which can beemployed to treat various conditions at the same time. In oneembodiment, one print head can deliver nonswellable hydrogel containingdental bleach while another print head can deliver swellable hydrogelcontaining medicaments used to manufacture the oral appliance to treatgum disease.

In other embodiments, the Dig 3 oral appliance can be utilized as adiagnostic tool for testing of fluids in the oral cavity. In theseembodiments, the hydrogel of the Dig3 oral appliance is absorptive bothon its internal and external surfaces and can therefore be easily usedto test the gingival crevicular fluids and/or saliva present in the oralcavity for diagnostic purposes. After the patient wears the Dig3 oralappliance, the oral appliance can be removed, placed into a containerand then sent to a lab for analysis. The Dig3 oral appliance can testoral fluids to do so over longer periods of time and is thussignificantly more effective than the fluid spot testing currently usedin the prior art. In some embodiments, in place of or in addition to themedicament, the oral appliance can comprise absorptive material that canretain the sample (e.g., cells, fluid (e.g., blood saliva), etc.), suchmaterial includes, but is not limited to, absorptive hydrogels,absorptive sponge, or sponge-like material, polyvinyl acetate (PVA),polyurethane (PU), cellulose, polyester, rayon, cotton or a combinationthereof.

The dimensions of the oral appliance, among other things, will depend onthe target treatment site and whether local or systemic delivery of themedicament is required. The oral appliance can be adapted to any sizeand shape to receive at least a portion of the teeth and/or soft tissueareas inside the mouth to deliver the medicament. For example, the oralappliance is designed to contour, support and hold the polymer gelmaterial and, in various embodiments, extends to at least themuco-gingival junction, or at least 2 mm to 5 mm buccally or linguallybeyond a gingival margin, or contact all or substantially all of one ormore teeth and/or soft tissue areas inside the mouth and adjacent buccaland lingual soft tissue areas.

In various embodiments, the oral appliance has a thickness of from about0.06 inches to about 0.2 inches, a depth of at least about 1 mm to about5 mm and a width of from about 1 mm to about 10 mm. In certainembodiments, the thickness of surface of the oral appliance isincrementally configured for treatment of a gum disease.

Material of Oral Appliance

The material of the oral appliance can be any material that can hold andrelease the medicament or in some embodiments, retain a sample (e.g.,blood, saliva, cells, etc.). In various embodiments, the material fromwhich the oral appliance can be manufactured includes swellable polymermaterials, such as, for example gels, hydrogels, polymer brushes orcombinations thereof.

In various embodiments, polymer gels, hydrogels, and brush polymers canbe formulated to have varying degrees of swelling ability. Thus, atreatment that involves the application of pressure to soft tissues ofthe mouth can be accommodated through the specific formulation of Dig2materials to incorporate the desired amount or percentage of swellingduring treatment. In some embodiments, the polymer comprises 20 wt % to90 wt % of the formulation.

In various embodiments, the molecular weight of the gel can be varied asdesired. The choice of method to vary molecular weight is typicallydetermined by the composition of the gel (e.g., polymer, versusnon-polymer). For example in various embodiments, when the gel comprisesone or more polymers, the degree of polymerization can be controlled byvarying the amount of polymer initiators (e.g. benzoyl peroxide),organic solvents or activator (e.g. DMPT), crosslinking agents,polymerization agent, incorporation of chain transfer or chain cappingagents and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel that includes a high molecular weight polymer tends tocoagulate or solidify more quickly than a polymeric composition thatincludes a low-molecular weight polymer. Polymeric gel formulations thatinclude high molecular weight polymers also tend to have a highersolution viscosity than a polymeric gel that includes low-molecularweight polymers. In various embodiments, the molecular weight of thepolymer can be a wide range of values. The average molecular weight ofthe polymer can be from about 1000 to about 10,000,000; or about 1,000to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 toabout 100,000; or about 20,000 to 50,000 g/mol.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and may have a longerdegradation time). Typically, when the polymers have similar componentsbut different molecular weights, a gel with a high molecular weightprovides a stronger matrix and the matrix takes more time to degrade. Incontrast, a gel with a low molecular weight degrades more quickly andprovides a softer matrix. In various embodiments, the gel has amolecular weight, as shown by the inherent viscosity, from about 0.10dL/g to about 1.2 dL/g or from about 0.10 dug to about 0.40 dug. OtherIV ranges include but are not limited to about 0.05 to about 0.15 dL/g,about 0.10 to about 0.20 dug, about 0.15 to about 0.25 dug, about 0.20to about 0.30 dug, about 0.25 to about 0.35 dug, about 0.30 to about0.35 dug, about 0.35 to about 0.45 dL/g, about 0.40 to about 0.45 dL/g,about 0.45 to about 0.55 dL/g, about 0.50 to about 0.70 dL/g, about 0.60to about 0.80 dL/g, about 0.70 to about 0.90 dL/g, about 0.80 to about1.00 dL/g, about 0.90 to about 1.10 dL/g, about 1.0 to about 1.2 dL/g,about 1.1 to about 1.3 dL/g, about 1.2 to about 1.4 dL/g, about 1.3 toabout 1.5 dL/g, about 1.4 to about 1.6 dL/g, about 1.5 to about 1.7dL/g, about 1.6 to about 1.8 dL/g, about 1.7 to about 1.9 dL/g, andabout 1.8 to about 2.1 dL/g.

In some embodiments, when the polymer materials have differentchemistries (e.g., high MW DLG 5050 and low MW DL), the high MW polymermay degrade faster than the low MW polymer.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, or from about 15 cps to about 75 cps at room temperature. Thegel may optionally have a viscosity enhancing agent such as, forexample, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl methylcellulose, carboxymethylcellulose and salts thereof,Carbopol, poly-(hydroxyethylmethacrylate),poly-(methoxyethylmethacrylate), poly(methoxyethoxyethyl methacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400,PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG3350, PEG 4500, PEG 8000 or combinations thereof.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. In other embodiments, the hydrogel material can hold some or allof the liquid medicament when the hydrogel material is hypo-saturated,saturated, or supersaturated with liquid medicament. There are manyadvantages resulting from using hydrogel in making the oral appliancesdescribed herein. Generally, hydrogel materials provide an effectivecontact medium for gum compression and for holding and diffusion of themedicament selected for treatment. The above can hold the sample (e.g.,saliva, blood, cells, etc.) when the oral appliance is removed and thenthe oral appliance can be sent to the lab for testing.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid andpoly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol(for example, PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins suchas polyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with medicament. In one embodiment, themicrospheres provide for a sustained release of the medicament. In yetanother embodiment, the gel, which is biodegradable, prevents themicrospheres from releasing the medicament; the microspheres thus do notrelease the medicament until they have been released from the gel.Dispersed within the gel may be a plurality of microspheres thatencapsulate the desired therapeutic agent. Certain of these microspheresdegrade once released from the gel, thus releasing the medicament.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type in the oral cavity, and hencedisperse the medicament. In some situations, this may be desirable whilein others, it may be more desirable to keep the medicament tightlyconstrained to a well-defined target site.

In various embodiments, also useful material for preparing the oralappliances described in this disclosure comprise reactive segmentedblock copolymers containing hydrophilic domain(s) and showing goodsurface properties when the block copolymer is covalently bound tosubstrates containing complimentary functionality. The hydrophilicdomain(s) will comprise at least one hydrophilic monomer, such as, HEMA,glyceryl methacrylate, methacrylic acid (“MAA”), acrylic acid (“AA”),methacrylamide, acrylamide, N,N′-dimethylmethacrylamide, orN,N′-dimethylacrylamide; copolymers thereof; hydrophilic prepolymers,such as ethylenically unsaturated poly(alkylene oxide)s, cyclic lactamssuch as N-vinyl-2-pyrrolidone (“NVP”), or derivatives thereof. Stillfurther examples are the hydrophilic vinyl carbonate or vinyl carbamatemonomers. Hydrophilic monomers can be nonionic monomers, such as2-hydroxyethyl methacrylate (“HEMA”), 2-hydroxyethyl acrylate (“HEA”),2-(2-ethoxyethoxy)ethyl(meth)acrylate, glyceryl(meth)acrylate,poly(ethylene glycol(meth)acrylate), tetrahydrofurfuryl(meth)acrylate,(meth)acrylamide, N,N′-dimethylmethacrylamide, N,N′-dimethylacrylamide(“DMA”), N-vinyl-2-pyrrolidone (or other N-vinyl lactams), N-vinylacetamide, and combinations thereof. Still further examples ofhydrophilic monomers are the vinyl carbonate and vinyl carbamatemonomers disclosed in U.S. Pat. No. 5,070,215, and the hydrophilicoxazolone monomers disclosed in U.S. Pat. No. 4,910,277. The contents ofthese patents are incorporated herein by reference. The hydrophilicmonomer also can be an anionic monomer, such as2-methacryloyloxyethylsulfonate salts. Substituted anionic hydrophilicmonomers, such as from acrylic and methacrylic acid, can also beutilized wherein the substituted group can be removed by a facilechemical process.

The polymer gel material can comprise orally soluble or insolublepolymers. For example, the polymer gel material may be designed to beinsoluble in the oral environment, yet still release the medicament thatis coated on or internally imbedded in the polymer gel material.Alternatively, the polymer gel material could be designed such that thepolymer and one or more medicaments could dissolve in the oralenvironment. Such orally dissolvable polymer gel material would releaseimbedded medicaments as the polymer is dissolved away by the flow ofsaliva. Various polymers whether soluble, insoluble, semi-soluble orcombinations of these may be used to create a polymer gel material withspecific active ingredient releasing capabilities. Many plastics andplastic combinations are suitable for this application. A few examplesof possible plastics include: polyacrylates, polyamide-imide, phenolic,nylon, nitrile resins, petroleum resins, fluoropolymers, copolyvidones(copovidones), epoxy, melamine-formaldehyde, diallyl phthalate, acetal,coumarone-indene, acrylics, acrylonitrile-butadiene-styrene, alkyds,cellulosics, polybutylene, polycarbonate, polycaprolactones,polyethylene, polyimides, polyphenylene oxide, polypropylene,polystyrene, polyurethanes, polyvinyl acetates, polyvinyl chloride,poly(vinyl alcohol-co ethylene), styrene acrylonitrile, sulfonepolymers, saturated or unsaturated polyesters, urea-formaldehyde, or anylike plastics.

In one embodiment the hydrogel material may comprise a backing material(e.g., a closed cell plastic backing material) to minimize elution ofthe medicament from the oral appliance, into the oral cavity to minimizeingestion by the patient and/or irritation of the oral cavity tissues.The hyrogels material can be constructed to increase release of themedicament to give a bolus dose or the polymer gel material may bedesigned to prevent medicament from spilling out of the hydrogelmaterial and allow the medicament to pass through the polymer gelhydrogel over time to obtain a sustained release profile. In otherwords, in various embodiments, the hydrogel material may have aninternal structural spacing sized relative to the viscosity of themedicament to absorb and allow the composition to pass therethrough toachieve the desired medicament release profile, for example, immediaterelease, bolus release, sustained or controlled release.

The dimensions of the polymer material (e.g., gel, hydrogel, etc.),among other things, will depend on the target treatment site and whetherlocal or systemic delivery of the medicament is required as well as thetype of medicament release profile to achieve. The oral applianceprepared is prepared primarily of polymer material and can be adapted toany size and shape required to receive at least a portion of the teethand/or soft tissue areas inside the mouth to deliver the medicament. Forexample, the polymer material may, in various embodiments, extend to atleast the muco-gingival junction, or at least 2 mm to 5 mm buccally orlingually beyond a gingival margin, or contact all or substantially allof one or more teeth and/or soft tissue areas inside the mouth andadjacent buccal and lingual soft tissue areas. In various embodiments,the polymer material contacts all or substantially all of one or moreteeth and/or soft tissue areas inside the mouth. In various embodiments,the polymer material contacts the soft tissue and teeth at or near agingival margin or sulcus. In various embodiments, the polymer materialhas a thickness of from about 0.06 inches to about 0.2 inches, a depthof at least about 1 mm to about 5 mm and a width of from about 1 mm toabout 10 mm.

Medicaments

The polymer material contains one or more medicaments coated, layered onit, impregnated within it at the same or different areas to form amonolithic oral appliance. In various embodiments, some areas of thepolymer material do not contain one or more medicaments, and the polymermaterial may function to hold or lock a portion of the polymer material(e.g., gel, hydrogel, etc.) in place so that other portions of thepolymer material can contact the appropriate target site. Thus, in someembodiments, the polymer material may contain one or more medicamentsdisposed in or on it throughout the whole polymer material. In otherembodiments, one or more portions of the polymer material do not containany medicament disposed in or on it. The term “medicament” as usedherein is generally meant to refer to any substance that alters thephysiology of a patient. The term “medicament” may be usedinterchangeably herein with the terms “drug” “therapeutic agent”,“therapeutically effective amount”, or “active pharmaceuticalingredient”. It will be understood that a “medicament formulation” mayinclude more than one therapeutic agent, wherein exemplary combinationsof therapeutic agents include a combination of two or more medicaments.The medicament can also include cells, where the device (e.g., oralappliance) can be seeded with the cells, for example, gingival cells orgingival tissue, bone cells, cartilage cells, bone tissue, cartilagetissue so that the device can repair or replace tissue in the treatmentarea.

The medicament may be in powder, liquid, solid, solution, or suspension(e.g., gel) form and disposed on or impregnated in the polymer material.This may occur during manufacture of the polymer material or it mayoccur after the polymer material is made. For example, on the corepolymer material, the medicament may be layered by solution orsuspension layering or powder layering techniques. In solution orsuspension layering, the medicament and any inactive ingredients(excipients, binders, etc.) are suspended or dissolved in water or anorganic solvent. The resulting liquid is sprayed onto the outside ofpolymer material to make the polymer material have the desired potency.Solution or suspension layering may be conducted using a wide variety ofprocess techniques, for example, by fluidized bed, Wurster bottom spraytechniques, or the like. When the desired potency has been achieved, thepolymer material is dried to the desired residual moisture content.Powdered layering involves the application of a dry powder to thepolymer material. The powder may contain the drug, or may includeexcipients such as a binder, flow aid, inert filler, or the like. In thepowder layering technique a pharmaceutically acceptable liquid, whichmay be water, organic solvent, with or without a binder and/orexcipients, is applied to the polymer material while applying the drypowder until the desired potency is achieved. When the desired potencyhas been achieved, the polymer material may be dried to the desiredmoisture content.

In various embodiments, the medicament may be encapsulated in a lipidbilayer and then impregnated, coated or layered on or into the polymermaterial. In various embodiments, the medicament can bemicro-encapsulated into a carrier having a positive or negative charge,such as for example, a Novasome® (available from IGI) to increaseabsorption of the medicament or cause it to have sustain releaseproperties to release the medicament over hours (e.g., 1-24 hours orlonger). The Novasome® can be made using amphiphiles, which include avariety of fatty alcohols and acids to give the medicament the desiredcharged and release property. It will be understood that other ionicallycharged materials can be used as well.

In various embodiments, medicaments can now be used at lower doses asthe polymer material improves contact with the target treatment area(s)of the teeth and/or soft tissue. Thus, less dose of the medicament canbe used because more effective concentration of medicament at the one ormore target sites is achieved over time.

Examples of medicaments include, but are not limited to,anti-inflammatory agents, anti-infective agents (e.g., antiviral,antibacterial, antifungal agents, etc.), tissue and bone growth factors,pain management medication (e.g., analgesics, anesthetics, etc.)antineoplastic agents, tooth whitening agents, breath fresheners,anticalculus agents, antineoplastic agents, oral dermatologics,selective H-2 antagonists, anticaries agents, nutrients, vitamins,minerals, herbal products, or mixtures thereof.

The medicament may be a systemic medicament such as thyroid drug, e.g.,anti-thyroid agents or thyrostatic substances that are compounds usefulfor the treatment of thyroid diseases, including hormones such asthyroxine (T4), triiodothyronine (T3); propylthiouracil; methimazole;and so forth.

In various embodiments, the polymer material may contain more than onemedicament. However, in another embodiment, combination therapy willinvolve use of a single safe and effective amount of the medicament. Forexample the method may further comprise subsequently administering oneor more additional oral appliances, each containing a medicament that isdifferent from the medicament contained in the earlier oral appliance.In this way, a series of customized treatment regimens can be providedto the patient. This provides for a “mix and match” medicament regimenwith dose adjustment capability and provides the added advantage ofallowing the health professional complete control to administer onlythose medicaments at the desired strength believed to be appropriate forthe disease or condition being treated.

The amount of medicament contained within the polymer material, willvary widely depending on the effective dosage required and rate ofrelease from the polymer material and the length of the desired deliveryinterval. The dosage administered to the patient can be single ormultiple doses and will vary depending upon a variety of factors,including the agent's pharmacokinetic properties, patient conditions andcharacteristics (sex, age, body weight, health, size, etc.), extent ofsymptoms, concurrent treatments, frequency of treatment and the effectdesired.

In various embodiments, the polymer material is designed to release themedicament as a bolus dose of the medicament, a single dose of themedicament, or multiple doses of the medicament all preloaded with aspecific dosage at the manufacturing facility.

Anti-inflammatory agents are of particular interest as it is believedthat they serve not only to reduce inflammation but, in doing so, canalso have a variety of other beneficial effects that may eliminate theneed for or minimize the amount of additional medicaments. For example,if a patient is suffering from pain and inflammation, administration ofan anti-inflammatory agent will alleviate inflammation and the tissue,once back to normal may no longer exert pressure on nerves and thus theneed for additional pain medication may be minimized or eliminatedentirely.

Suitable anti-inflammatory agents to treat and/or reduce inflammationinclude steroidal and/or non-steroidal anti-inflammatories. Exemplaryanti-inflammatory agents include by way of example and not limitation,alclofenac; alclometasone dipropionate; algestone acetonide; alendronatesodium; alpha amylase; amcinafal; amcinafide; amcinonide; amfenacsodium; amiprilose hydrochloride; anakinra; anirolac; anitrazafen;apazone; balsalazide disodium; beclomethasone diproprionate; bendazac;benoxaprofen; benzydamine hydrochloride; betamethasone; bromelains;broperamole; budesonide; carprofen; cicloprofen; cintazone; cliprofen;clobetasol propionate; clobetasone butyrate; clopirac; cloticasonepropionate; cormethasone acetate; cortisone acetate; cortodoxone;deflazacort; desonide; desoximetasone; dexamethasone dipropionate;diclofenac potassium; diclofenac sodium; diflorasone diacetate;diflumidone sodium; diflunisal; difluprednate; diftalone; dimethylsulfoxide; drocinonide; endrysone; enlimomab; enolicam sodium;epirizole; etodolac; etofenamate; felbinac; fenamole; fenbufen;fenclofenac; fenclorac; fendosal; fenpipalone; fentiazac; flazalone;fluazacort; fludrocortisone; flufenamic acid; flumizole; flunisolideacetate; flunixin; flunixin meglumine; fluocinonide; fluocinoloneacetonide; fluocortin butyl; fluorometholone acetate; fluquazone;flurandrenolide; flurbiprofen; fluretofen; fluticasone propionate;furaprofen; furobufen; halcinonide; halobetasol propionate; halopredoneacetate; hydrocortisone; ibufenac; ibuprofen; ibuprofen aluminum;ibuprofen piconol; ilonidap; indomethacin; indomethacin sodium;indoprofen; indoxole; intrazole; isoflupredone acetate; isoxepac;isoxicam; ketoprofen; lofemizole hydrochloride; lomoxicam; loteprednoletabonate; meclofenamate sodium; meclofenamic acid; meclorisonedibutyrate; medrysone; mefenamic acid; mesalamine; meseclazone;methylprednisolone suleptanate; momiflumate; nabumetone; naproxen;naproxen sodium; naproxol; nimazone; nilutamide; olsalazine sodium;orgotein; orpanoxin; oxaprozin; oxyphenbutazone; pamidronate disodium;paramethasone; paranyline hydrochloride; pentosan polysulfate sodium;phenbutazone sodium glycerate; pirfenidone; piroxicam; piroxicamcinnamate; piroxicam olamine; pirprofen; prednazate; prednisolone;prifelone; prodolic acid; proquazone; proxazole; proxazole citrate;rimexolone; romazarit; salcolex; salnacedin; salsalate; sanguinariumchloride; seclazone; sermetacin; sudoxicam; sulindac; suprofen;talmetacin; talniflumate; talosalate; tebufelone; tenidap; tenidapsodium; tenoxicam; tesicam; tesimide; tetrydamine; tiopinac; tixocortolpivalate; tolmetin; tolmetin sodium; triamcinelone; triclonide;triflumidate; zidometacin; zomepirac sodium or combinations thereof.

Anti-inflammatory agents include steroidal agents orglucocorticosteroids. Phospholipase A2 (“PLA2”) is a lipolytic enzymethat has been implicated as a possible mediator of inflammation.Specifically, PLA2 hydrolyses the 2-acyl position ofglycerophospholipids, liberating free-fatty acids, mainly arachidonicacid. Subsequently, it is believed that arachidonic acid is convertedinto a variety of proinflammatory cicosanoids. Glucocorticosteroids areknown to stop or reduce the suggested mechanisms of inflammation thatinvolves the activation of the arachidonic acid cascade, which resultsin the liberation of a variety of proinflammatory eicosanoids byinducing lipocortin that inhibits PLA2. This provides a significantadvantage over non-steroidal anti-inflammatory agents that enter thecascade much later.

Suitable glucocorticosteroids include, but are not limited to,alclometasone diproprionate, alendronate sodium, amcinonide,beclomethasone diproprionate, betamethasone, budesonide, clobetasolpropionate, cortisone, dexamethasone, diflorasone diacetate,hydrocortisone, fludrocortisone; flunisolide acetate, fluocinoloneacetonide, fluocinonide, fluorometholone acetate, flurandrenolide,halcinonide, medrysone; methylprednisone suleptanate, pamidronate,paramethasone, prednisolone, nilutamide, triamcinelone, or combinationsthereof.

Dexamethasone is of particular interest for use as an anti-inflammatoryto treat orofacial diseases. Besides its anti-inflammatory property,dexamethasone can be delivered to up-regulate certain enzyme activities.Specifically dexamethasone can be used to increase or up-regulatealkaline phosphotase activity in regenerating human periodontal cells.

Exemplary anti-infective agents to treat infection include by way ofexample and not limitation, antibacterial agents; quinolones and inparticular fluoroquinolones (e.g., norfloxacin, ciprofloxacin,lomefloxacin, ofloxacin, etc.), aminoglycosides (e.g., gentamicin,tobramycin, etc.), glycopeptides (e.g., vancomycin, etc.), lincosamides(e.g., clindamycin), cephalosporins (e.g., first, second, thirdgeneration) and related beta-lactams, macrolides (e.g., azithromycin,erythromycin, etc.), nitroimidazoles (e.g., metronidazole), penicillins,polymyxins, tetracyclines, or combinations thereof.

Other exemplary antibacterial agents include, by way of illustration andnot limitation, acedapsone; acetosulfone sodium; alamecin; alexidine;amdinocillin; amdinocillin pivoxil; amicycline; amifloxacin; amifloxacinmesylate; amikacin; amikacin sulfate; aminosalicylic acid;aminosalicylate sodium; amoxicillin; amphomycin; ampicillin; ampicillinsodium; apalcillin sodium; apramycin; aspartocin; astromicin sulfate;avilamycin; avoparcin; azithromycin; azlocillin; azlocillin sodium;bacampicillin hydrochloride; bacitracin; bacitracin methylenedisalicylate; bacitracin zinc; bambermycins; benzoylpas calcium;berythromycin; betamicin sulfate; biapenem; biniramycin; biphenaminehydrochloride; bispyrithione magsulfex; butikacin; butirosin sulfate;capreomycin sulfate; carbadox; carbenicillin disodium; carbenicillinindanyl sodium; carbenicillin phenyl sodium; carbenicillin potassium;carumonam sodium; cefaclor, cefadroxil; cefamandole; cefamandole nafate;cefamandole sodium; cefaparole; cefatrizine; cefazaflur sodium;cefazolin; cefazolin sodium; cefbuperazone; cefdinir; cefepime; cefepimehydrochloride; cefetecol; cefixime; cefmenoxime hydrochloride;cefmetazole; cefmetazole sodium; cefonicid monosodium; cefonicid sodium;cefoperazone sodium; ceforanide; cefotaxime sodium; cefotetan; cefotetandisodium; cefotiam hydrochloride; cefoxitin; cefoxitin sodium;cefpimizole; cefpimizole sodium; cefpiramide; cefpiramide sodium;cefpirome sulfate; cefpodoxime proxetil; cefprozil; cefroxadine;cefsulodin sodium; ceftazidime; ceftibuten; ceftizoxime sodium;ceftriaxone sodium; cefuroxime; cefuroxime axetil; cefuroxime pivoxetil;cefuroxime sodium; cephacetrile sodium; cephalexin; cephalexinhydrochloride; cephaloglycin; cephaloridine; cephalothin sodium;cephapirin sodium; cephradine; cetocycline hydrochloride; cetophenicol;chloramphenicol; chloramphenicol palmitate; chloramphenicol pantothenatecomplex; chloramphenicol sodium succinate; chlorhexidine phosphanilate;chloroxylenol; chlortetracycline bisulfate; chlortetracyclinehydrochloride; cinoxacin; ciprofloxacin; ciprofloxacin hydrochloride;cirolemycin; clarithromycin; clinafloxacin hydrochloride; clindamycin;clindamycin hydrochloride; clindamycin palmitate hydrochloride;clindamycin phosphate; clofazimine; cloxacillin benzathine; cloxacillinsodium; cloxyquin; colistimethate sodium; colistin sulfate; coumermycin;coumermycin sodium; cyclacillin; cycloserine; dalfopristin; dapsone;daptomycin; demeclocycline; demeclocycline hydrochloride; demecycline;denofungin; diaveridine; dicloxacillin; dicloxacillin sodium;dihydrostreptomycin sulfate; dipyrithione; dirithromycin; doxycycline;doxycycline calcium; doxycycline fosfatex; doxycycline hyclate; droxacinsodium; enoxacin; epicillin; epitetracycline hydrochloride;erythromycin; erythromycin acistrate; erythromycin estolate;erythromycin ethylsuccinate; erythromycin gluceptate; erythromycinlactobionate; erythromycin propionate; erythromycin stearate; ethambutolhydrochloride; ethionamide; fleroxacin; floxacillin; fludalanine;flumequine; fosfomycin; fosfomycin tromethamine; fumoxicillin;furazolium chloride; furazolium tartrate; fusidate sodium; fusidic acid;ganciclovir and ganciclovir sodium; gentamicin sulfate; gloximonam;gramicidin; haloprogin; hetacillin; hetacillin potassium; hexedine;ibafloxacin; imipenem; isoconazole; isepamicin; isoniazid; josamycin;kanamycin sulfate; kitasamycin; levofuraltadone; levopropylcillinpotassium; lexithromycin; lincomycin; lincomycin hydrochloride;lomefloxacin; lomefloxacin hydrochloride; lomefloxacin mesylate;loracarbef; mafenide; meclocycline; meclocycline sulfosalicylate;megalomicin potassium phosphate; mequidox; meropenem; methacycline;methacycline hydrochloride; methenamine; methenamine hippurate;methenamine mandelate; methicillin sodium; metioprim; metronidazolehydrochloride; metronidazole phosphate; mezlocillin; mezlocillin sodium;minocycline; minocycline hydrochloride; mirincamycin hydrochloride;monensin; monensin sodiumr; nafcillin sodium; nalidixate sodium;nalidixic acid; natainycin; nebramycin; neomycin palmitate; neomycinsulfate; neomycin undecylenate; netilmicin sulfate; neutramycin;nifuiradene; nifuraldezone; nifuratel; nifuratrone; nifurdazil;nifurimide; nifiupirinol; nifurquinazol; nifurthiazole; nitrocycline;nitrofurantoin; nitromide; norfloxacin; novobiocin sodium; ofloxacin;onnetoprim; oxacillin and oxacillin sodium; oximonam; oximonam sodium;oxolinic acid; oxytetracycline; oxytetracycline calcium; oxytetracyclinehydrochloride; paldimycin; parachlorophenol; paulomycin; pefloxacin;pefloxacin mesylate; penamecillin; penicillins such as penicillin gbenzathine, penicillin g potassium, penicillin g procaine, penicillin gsodium, penicillin v, penicillin v benzathine, penicillin v hydrabamine,and penicillin v potassium; pentizidone sodium; phenyl aminosalicylate;piperacillin sodium; pirbenicillin sodium; piridicillin sodium;pirlimycin hydrochloride; pivampicillin hydrochloride; pivampicillinpamoate; pivampicillin probenate; polymyxin b sulfate; porfiromycin;propikacin; pyrazinamide; pyrithione zinc; quindecamine acetate;quinupristin; racephenicol; ramoplanin; ranimycin; relomycin;repromicin; rifabutin; rifametane; rifamexil; rifamide; rifampin;rifapentine; rifaximin; rolitetracycline; rolitetracycline nitrate;rosaramicin; rosaramicin butyrate; rosaramicin propionate; rosaramicinsodium phosphate; rosaramicin stearate; rosoxacin; roxarsone;roxithromycin; sancycline; sanfetrinem sodium; sarmoxicillin;sarpicillin; scopafungin; sisomicin; sisomicin sulfate; sparfloxacin;spectinomycin hydrochloride; spiramycin; stallimycin hydrochloride;steffimycin; streptomycin sulfate; streptonicozid; sulfabenz;sulfabenzamide; sulfacetamide; sulfacetamide sodium; sulfacytine;sulfadiazine; sulfadiazine sodium; sulfadoxine; sulfalene;sulfamerazine; sulfameter; sulfamethazine; sulfamethizole;sulfamethoxazole; sulfamonomethoxine; sulfamoxole; sulfanilate zinc;sulfanitran; sulfasalazine; sulfasomizole; sulfathiazole; sulfazamet;sulfisoxazole; sulfisoxazole acetyl; sulfisboxazole diolamine;sulfomyxin; sulopenem; sultamricillin; suncillin sodium; talampicillinhydrochloride; teicoplanin; temafloxacin hydrochloride; temocillin;tetracycline; tetracycline hydrochloride; tetracycline phosphatecomplex; tetroxoprim; thiamphenicol; thiphencillin potassium;ticarcillin cresyl sodium; ticarcillin disodium; ticarcillin monosodium;ticlatone; tiodonium chloride; tobramycin; tobramycin sulfate;tosufloxacin; trimethoprim; trimethoprim sulfate; trisulfapyrimidines;troleandomycin; trospectomycin sulfate; tyrothricin; vancomycin;vancomycin hydrochloride; virginiamycin; zorbamycin; or combinationsthereof.

Exemplary muscle relaxants include by way of example and not limitation,alcuronium chloride, atracurium bescylate, baclofen, carbolonium,carisoprodol, chlorphenesin carbamate, chlorzoxazone, cyclobenzaprine,dantrolene, decamethonium bromide, fazadinium, gallamine triethiodide,hexafluorenium, meladrazine, mephensin, metaxalone, methocarbamol,metocurine iodide, pancuronium, pridinol mesylate, styramate,suxamethonium, suxethonium, thiocolchicoside, tizanidine, tolperisone,tubocuarine, vecuronium, and combinations thereof. Exemplary musclerelaxants include by way of example and not limitation, alcuroniumchloride, atracurium bescylate, baclofen, carbolonium, carisoprodol,chlorphenesin carbamate, chlorzoxazone, cyclobenzaprine, dantrolene,decamethonium bromide, fazadinium, gallamine triethiodide,hexafluorenium, meladrazine, mephensin, metaxalone, methocarbamol,metocurine iodide, pancuronium, pridinol mesylate, styramate,suxamethonium, suxethonium, thiocolchicoside, tizanidine, tolperisone,tubocuarine, vecuronium, or combinations thereof.

Exemplary analgesics include, but are not limited to, acetaminophen;alfentanil hydrochloride; aminobenzoate potassium; aminobenzoate sodium;anidoxime; anileridine; anileridine hydrochloride; anilopamhydrochloride; anirolac; antipyrine; aspirin; benoxaprofen; benzydaminehydrochloride; bicifadine hydrochloride; brifentanil hydrochloride;bromadoline maleate; bromfenac sodium; buprenorphine hydrochloride;butacetin; butixirate; butorphanol; butorphanol tartrate; carbamazepine;carbaspirin calcium; carbiphene hydrochloride; carfentanil citrate;ciprefadol succinate; ciramadol; ciramadol hydrochloride; clonixeril;clonixin; codeine; codeine phosphate; codeine sulfate; conorphonehydrochloride; cyclazocine; dexoxadrol hydrochloride; dexpemedolac;dezocine; diflunisal; dihydrocodeine bitartrate; dimefadane; dipyrone;doxpicomine hydrochloride; drinidene; enadoline hydrochloride;epirizole; ergotamine tartrate; ethoxazene hydrochloride; etofenamate;eugenol; fenoprofen; fenoprofen calcium; fentanyl citrate; floctafenine;flufenisal; flunixin; flunixin meglumine; flupirtine maleate;fluproquazone; fluradoline hydrochloride; flurbiprofen; hydromorphonehydrochloride; ibufenac; indoprofen; ketazocine; ketorfanol; ketorolacand ketorolac tromethamine; letimide hydrochloride; levomethadylacetate; levomethadyl acetate hydrochloride; levonantradolhydrochloride; levorphanol tartrate; lofemizole hydrochloride;lofentanil oxalate; lorcinadol; lomoxicam; magnesium salicylate;mefenamic acid; menabitan hydrochloride; meperidine hydrochloride;meptazinol hydrochloride; methadone hydrochloride; methadyl acetate;methopholine; methotrimeprazine; metkephamid acetate; mimbanehydrochloride; mirfentanil hydrochloride; molinazone; morphine sulfate;moxazocine; nabitan hydrochloride; nalbuphine hydrochloride; nalmexonehydrochloride; namoxyrate; nantradol hydrochloride; naproxen; naproxensodium; naproxol; nefopam hydrochloride; nexeridine hydrochloride;noracymethadol hydrochloride; ocfentanil hydrochloride; octazamide;olvanil; oxetorone fumarate; oxycodone; oxycodone hydrochloride;oxycodone terephthalate; oxymorphone hydrochloride; pemedolac;pentamorphone; pentazocine; pentazocine hydrochloride; pentazocinelactate; phenazopyridine hydrochloride; phenyramidol hydrochloride;picenadol hydrochloride; pinadoline; pirfenidone; piroxicam olamine;pravadoline maleate; prodilidine hydrochloride; profadol hydrochloride;propiram fumarate; propoxyphene hydrochloride; propoxyphene napsylate;proxazole; proxazole citrate; proxorphan tartrate; pyrroliphenehydrochloride; remifentanil hydrochloride; salcolex; salethamidemaleate; salicylamide; salicylate meglumine; salsalate; sodiumsalicylate; spiradoline mesylate; sufentanil; sufentanil citrate;talmetacin; talniflumate; talosalate; tazadolene succinate; tebufelone;tetrydamine; tifurac sodium; tilidine hydrochloride; tiopinac;tonazocine mesylate; tramadol hydrochloride; trefentanil hydrochloride;trolamine; veradoline hydrochloride; verilopam hydrochloride;volazocine; xorphanol mesylate; xylazine hydrochloride; zenazocinemesylate; zomepirac sodium; zucapsaicin or combinations thereof.

Exemplary anesthetics include by way of example and not limitation,aliflurane; benoxinate hydrochloride; benzocaine; biphenaminehydrochloride; bupivacaine hydrochloride; butamben; butamben picrate;chloroprocaine hydrochloride; cocaine; cocaine hydrochloride;cyclopropane; desflurane; dexivacaine; diamocaine cyclamate; dibucaine;dibucaine hydrochloride; dyclonine hydrochloride; enflurane; ether;ethyl chloride; etidocaine; etoxadrol hydrochloride; euprocinhydrochloride; fluroxene; halothane; isobutamben; isoflurane; ketaminehydrochloride; levoxadrol hydrochloride; lidocaine; lidocainehydrochloride; mepivacaine hydrochloride; methohexital sodium;methoxyflurane; midazolam hydrochloride; midazolam maleate; minaxolone;nitrous oxide; norflurane; octodrine; oxethazaine; phencyclidinehydrochloride; pramoxine hydrochloride; prilocaine hydrochloride;procaine hydrochloride; propanidid; proparacaine hydrochloride;propofol; propoxycaine hydrochloride; pyrrocaine; risocaine; rodocaine;roflurane; salicyl alcohol; sevoflurane; teflurane; tetracaine;tetracaine hydrochloride; thiamylal; thiamylal sodium; thiopentalsodium; tiletamine hydrochloride; zolamine hydrochloride; orcombinations thereof.

The polymer material can be saturated with one or more analgesics thatcan anesthetize the patients tooth and/or soft tissue area before thedental procedure is performed. In this way, the patient can place theoral appliance inside the oral cavity and the pre-filled oral applianceand polymer material will numb the particular site. When the patientvisits the dental professional, little delay can occur while waiting forthe area to numb. In this way, fast efficient dental procedures (e.g.,tooth fillings, tooth extractions, root canal, dental cleanings, etc.)can be performed without delay to the dental provider or patient.

The polymer material may contain one or more antineoplastic agents totreat cancer. Exemplary antineoplastic agents include by way of exampleand not limitation, acivicin; aclarubicin; acodazole hydrochloride;acrqnine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer, carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; ethiodized oil I 131; etoposide; etoposide phosphate;etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;fludarabine phosphate; fluorouracil; flurocitabine; fosquidone;fostriecin sodium; gemcitabine; gemcitabine hydrochloride; gold Au 198;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;interferon alpha-2a; interferon alpha-2b; interferon .alpha n1;interferon alpha n3; interferon beta Ia; interferon gamma Ib;iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole;leucovorin in combination with fluorouracil or methotrexate; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safmgol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;strontium chloride Sr 89; sulofenur; talisomycin; taxane; taxoid;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; topotecan hydrochloride; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride; or combinations thereof.

The polymer material may contain one or more oral care medicaments that,in various embodiments, provide a benefit to the patient, withoutdetriment to the oral surface to which it is applied. Examples of theoral conditions these medicaments address include, but, are not limitedto, appearance to the teeth, whitening, stain bleaching, stain removal,plaque removal, tartar removal, cavity prevention and treatment, toothrecalcification, oral infections, inflamed and/or bleeding gums, mucosalwounds, lesions, ulcers, aphthous ulcers, cold sores, tooth abscesses,gingivitis, periodontal disease, xerostomia, post-surgical dressings andthe elimination of mouth malodor.

For example, the tight fit of the oral appliance further forces themedicament, by its three dimensional form, out of the polymer materialto pool at the gingival margin but also causes to compress it and forceit into the gingival sulcus and into the periodontal pockets. This isprecisely where active periodontal disease is and where the medicamentwill be delivered. It is also an area with tremendous capillary bloodflow and absorption. Thus, if desired, a medicament can be used that canprovide systemic treatment, for example, for hypertension medication,diabetes medication, asthma medication.

In some embodiments, the friction, force or scratching from the oralappliance on or in the oral cavity will cause release of the medicamentat or near the target site.

Patients undergoing head and neck radiation treatment for cancer oftensuffer from high incidences of dental caries because of xerostomia (drymouth). Xerostomia may also be caused by salivary gland disease, variousmedications and other causes. The oral appliance, in variousembodiments, allows the patient to self administer a wide variety ofmedicaments comfortably, painlessly and in the convenience of their ownhome.

In various embodiments, suitable medicaments include any material thatis generally considered safe for use in the oral cavity and thatprovides changes to the overall appearance and/or health of the patient.The level of medicament is generally, unless specifically noted, fromabout 0.01% to about 50% or from about 0.1% to about 20% or from about0.5% to about 10% or from about 1% to about 7%, by weight of thecomposition.

The polymer material may comprise a safe and effective amount of one ormore whitening agents such as bleaching agents or abrasive agents.Generally the level of the bleaching agent is dependent on the availableoxygen or chlorine respectively that the molecule is configured forproviding to bleach the stain. The bleaching agent may be present atlevels from about 0.1% to about 20%, in another embodiment from about0.5% to about 9% and in another embodiment from about 3% to about 8%,and in yet another embodiment from about 4% to about 6%, by weight ofthe bleaching agent composition.

Typical bleaching agents suitable for use in the present applicationinclude but are not limited to, peroxides, metal chlorites, perborates,percarbonates, peroxyacids, persulfates, compounds that form thepreceding compounds in situ, and combinations thereof. Suitable peroxidecompounds include hydrogen peroxide, urea peroxide, calcium peroxide,carbamide peroxide, and mixtures thereof. In one embodiment thebleaching agent is carbamide peroxide. Suitable metal chlorites includecalcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite,sodium chlorite, potassium chlorite, and mixtures thereof. Additionalbleaching agents also include hypochlorite and chlorine dioxide. In oneembodiment the bleaching agent is selected from sodium chlorite,peroxide, sodium percarbonate, oxones, and mixtures thereof. Thestarting bleach agent can be aqueous or solid material.

The polymer material may comprise a safe and effective amount of ananticaries agent or mixtures thereof. In various embodiments, theanticaries agent can comprise xylitol, a fluoride ion source, andmixtures thereof. The fluoride ion source provides free fluoride ionsduring the use. Examples of fluoride ion sources include, but are notlimited to, sodium fluoride, stannous fluoride, indium fluoride, organicfluorides such as amine fluorides, and sodium monofluorophosphate orcombination thereof. In various embodiments, the medicament providesfrom about 50 ppm to 10,000 ppm or from about 100 to 3000 ppm offluoride ions that contact tooth surfaces.

In various embodiments, the polymer material may comprise a safe andeffective amount of at least one anticalculus agent. This amount isgenerally from about 0.01% to about 40% by weight of the composition, inanother embodiment from about 0.1% to about 25%, and in yet anotherembodiment from about 4.5% to about 20%, and in yet another embodimentfrom about 5% to about 15%, by weight of the composition. Theanticalculus agent should also be compatible with the other componentsof the composition.

The anticalculus agent can contain polyphosphates and salts thereof;polyamino propane sulfonic acid (AMPS) and salts thereof; polyolefinsulfonates and salts thereof; polyvinyl phosphates and salts thereof;polyolefin phosphates and salts thereof; diphosphonates and saltsthereof; phosphonoalkane carboxylic acid and salts thereof;polyphosphonates and salts thereof; polyvinyl phosphonates and saltsthereof; polyolefin phosphonates and salts thereof; polypeptides; andmixtures thereof. In one embodiment, the salts are alkali metal salts.In another embodiment the anticalculus agent is a pyrophosphate,polyphosphate, and mixtures thereof.

In various embodiments, the polymer material may comprise a safe andeffective amount of at least one selective H-2 antagonist. Selective H-2antagonists include, but are not limited to, cimetidine, etintidine,ranitidine, ICIA-5165, tiotidine, ORF-17578, lupitidine, donetidine,famotidine, roxatidine, pifatidine, lamtidine, BL-6548, BMY-25271,zaltidine, nizatidine, mifentidine, BMY-25368 (SKF-94482), BL-6341A,ICI-162846, ramixotidine, Wy-45727, SR-58042, BMY-25405, loxtidine,DA-4634, bisfentidine, sufotidine, ebrotidine, HE-30-256, D-16637,FRG-8813, FRG-8701, impromidine, L-643728, and HB-408, burimamide,metiamide or combination thereof.

In various embodiments, the polymer material may comprise a safe andeffective amount of at least one nutrient that may improve the conditionof the oral cavity and can be included in the polymer material.Nutrients include minerals, vitamins, oral nutritional supplements,enteral nutritional supplements, and mixtures thereof. Minerals include,but are not limited to, calcium, phosphorus, fluoride, zinc, manganese,potassium and mixtures thereof.

Vitamins can be included with minerals or used separately. Vitaminsinclude Vitamins C and D, thiamine, riboflavin, calcium pantothenate,niacin, folic acid, nicotinamide, pyridoxine, cyanocobalamin,para-aminobenzoic acid, bioflavonoids, and mixtures thereof.

Oral nutritional supplements may also be included in the polymermaterial. Oral nutritional supplements include amino acids, lipotropics,fish oil, and mixtures thereof. Amino acids include, but, are notlimited to L-Tryptophan, L-Lysine, Methionine, Threonine, Levocarnitineor L-carnitine and mixtures thereof. Lipotropics include, but, are notlimited to choline, inositol, betaine, linoleic acid, linolenic acid,and mixtures thereof. Fish oil contains large amounts of Omega-3 (N-3)polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoicacid. Antioxidants may be included such as, for example, Vitamin E,ascorbic acid, Uric acid, carotenoids, Vitamin A, flavonoids andpolyphenols, herbal antioxidants, melatonin, aminoindoles, lipoic acidsand mixtures thereof.

Enteral nutritional supplements include, but, are not limited to proteinproducts, glucose polymers, corn oil, safflower oil, medium chaintriglycerides, flax seed oil. Anti-pain or desensitizing agents can alsobe included in or on the polymer material. Such agents may include, butare not limited to, strontium chloride, potassium nitrate, natural herbssuch as gall nut, Asarum, Cubebin, Galanga, scutellaria, Liangmianzhen,Baizhi, etc.

The polymer material may contain one or more herbal products that occurin nature or come from plants. Some herbal medicaments include, but arenot limited to, chondroitin sulfate, echinacea, ephedra (also called mahuang), garlic, ginkgo biloba, ginseng, glucosamine, kava, melatonin,phytoestrogens (such as black cohosh, dong quai and soy), saw palmetto,bee pollen, St. John's wort, or a combination thereof.

Apart from the active medicament, the polymer material may optionallycontain bulking agents, disintegrants, binders and lubricants, andexcipients, which have no decisive effect on the delivery of activesubstances. Examples are, alginate, inter alia, bentonite (aluminasilica hydrate), silica, cellulose (normally microcrystalline cellulose)or cellulose derivatives, for example methylcellulose, sodiumcarboxymethylcellulose, sugars such as lactose, starches, for examplemaize starch or derivatives thereof, for example sodiumcarboxymethyl-starch, starch paste, phosphoric acid salts, for exampledi- or tricalcium phosphate, gelatin, stearic acid or suitable saltsthereof, for example magnesium stearate or calcium stearate, talc,colloidal silica and similar ancillary substances.

In an exemplary embodiment, a method of delivering a medicament to atleast a portion of teeth and/or soft tissue areas inside a mouth isprovided, the method comprising: providing an oral appliance comprisingan interior surface having a medicament disposed in or on at least aportion of and/or all of the interior surface of the oral appliance, theinterior surface being formed to fit contours of at least the portion ofthe teeth and/or soft tissue areas inside the oral cavity and beingconfigured for supporting and holding the medicament in contact with atleast the portion of the teeth and/or soft tissue areas inside the oralcavity to deliver the medicament. In other embodiments, the oralappliance comprises a polymer and at least one medicament.

The oral appliance can be used for treatment of diseases or conditionsrequiring therapy including whitening teeth. Treating or treatment of adisease refers to executing a protocol, which may include administeringone or more oral appliance to a human patient or the patient mayself-administer the oral appliance, in an effort to alleviate signs orsymptoms of the disease. Alleviation can occur prior to signs orsymptoms of the disease appearing, as well as after their appearance.Thus, “treating” or “treatment” includes “preventing” or “prevention” ofdisease. In addition, “treating” or “treatment” does not requirecomplete alleviation of signs or symptoms, does not require a cure, andspecifically includes protocols that have only a marginal effect on thepatient.

“Localized” delivery includes delivery where one or more medicamentscontact the tooth and/or soft tissue areas, for example, the gingivalmargin of the mouth or a region of the inside of the mouth, or in closeproximity thereto. “Targeted delivery” includes delivery of one or moremedicaments at the target site as needed for treatment of the disease orcondition including cosmetic applications, for example, whitening teethor removing stains.

The oral appliance may be transparent, disposable and/or sterilizable.In various embodiments, one or more components of the device aresterilized by radiation in a terminal sterilization step in the finalpackaging. Terminal sterilization of a product provides greaterassurance of sterility than from processes such as an aseptic process,which require individual product components to be sterilized separatelyand the final package assembled in a sterile environment. Other methodsmay also be used to sterilize one or more components of the oralappliance, including, but not limited to, E-beam radiation, gammaradiation, gas sterilization, such as, for example, with ethylene oxideor steam sterilization.

The oral appliance may be used for localized and/or targeted delivery ofthe medicament to a patient to treat a disease or condition. Examples ofdiseases or conditions include, but, are not limited to, whitening,stain bleaching, stain removal, plaque removal, tartar removal, cavityprevention and treatment, tooth recalcification, oral infections,inflamed and/or bleeding gums, mucosal wounds, lesions, ulcers, aphthousulcers, cold sores, tooth abscesses, gingivitis, periodontal disease,xerostomia and the elimination of mouth malodor. Some systemic diseasesor conditions include, but are not limited to, hypertension, TMJ,migraines, GI ulcers, cardiac conditions, diabetes, neoplastic diseases,oral dermatologic diseases (e.g., lichen planus), hypothyroidism,hyperthyroidism, arthritis, or the like or combinations thereof.

Computer Implemented System

In various embodiments, the present disclosure provides a computerimplemented method of making an oral appliance. The method comprisescreating a digital record of a patient's oral cavity, the Base Image(BI), by obtaining a digital image of at least a portion of the teeth,and/or soft tissue of the oral cavity by using an imaging device. TheBase Image is additively overlayed to create a first digital image,Dig1. Subsequently, a second digital image, Dig2, comprising at least aportion of the teeth and/or soft tissue of the oral cavity in need oftreatment is subtractively generated. Thereafter, the first digitalimage, Dig1, and the second digital image, Dig2, are combined to form athird digital image, Dig3, of the oral cavity treatment area and thethird digital image is then stored in the computer and used formanufacture.

In some embodiments, there is a computer implemented method of producingan oral appliance pre-loaded with at least one medicament using acomputer, comprising: using the Base Image of the digital image of thepatient's mouth, generating first digital data representing an overlayof at least a portion of the teeth and/or soft tissues areas of the oralcavity of a patient, generating second digital data by performing adigital segmentation of at least a portion of the teeth and/or softtissues areas of the oral cavity to determine discrete regions of theoral cavity in need of treatment, combining the first digital data andthe second digital data to form third digital data from which the oralappliance can be produced, wherein the third digital data comprisespositions for at least one medicament to be placed at the discreteregions in the oral cavity in need of treatment.

In other embodiments, a computer-implemented method is provided forcreating a treatment plan for delivering a medicament to at least aportion of the teeth and/or soft tissue areas inside the oral cavity.The computer-implemented method comprises generating a first digitaldata, Dig1, representing at least a portion of the teeth and/or softtissues areas of the oral cavity of a patient from the Base Image.Subsequently, a second digital data, Dig2, is generated by performingvia the computer a digital segmentation of at least a portion of theteeth and/or soft tissues areas of the oral cavity comprising discreteregions of the oral cavity in need of treatment. The first digital data,Dig1, and the second digital data, Dig2, are then combined via computerto form the third digital data, Dig3, from which the oral appliance canbe produced, wherein the oral appliance has at least one medicamentpositioned at the discrete regions requiring treatment in the oralcavity.

In various embodiments, a computer based system further comprisescreating a virtual 3D image of the oral appliance indicating thediscrete regions requiring treatment in the oral cavity; displaying on adisplay the virtual 3D image and performing interactive treatment plansincluding the selection of the at least one medicament. Imaging devicesutilized to generate the various digital data sets include, withoutlimitations, a digital camera, X-ray device, hand-held 3-D scanner,laser scanner, computerized tomography (CT) scanner, magnetic resonanceimaging (MRI) scanner, coordinate measuring machine, destructive scanneror ultrasound scanner, generating first digital data, Dig1, representingat least a portion of the teeth and/or soft tissues areas of the oralcavity of a patient based on an imaging device image (Base Image),generating second digital data, Dig2, by performing via the computer adigital segmentation of at least a portion of the teeth and/or softtissues areas of the oral cavity comprising discrete regions of the oralcavity in need of treatment, combining via the computer the firstdigital data, Dig1, and the second digital data, Dig2, to form thirddigital data, Dig3, from which the oral appliance can be produced havingat least one medicament positioned at the discrete regions requiringtreatment in the oral cavity

In other embodiments, the three-dimensional representation of the thirddigital data, Dig3, is stored in a format suitable for use by amanufacturer to produce the oral appliance pre-loaded with at least onemedicament at areas targeted for treatment. A stereolithographyapparatus comprising at least two print heads can be used to manufacturethe oral appliances described in this disclosure. As discussed above,the first print head can be configured to deliver a first chemicalcomposition according to the first digital data, Dig1, and the secondprint head can be configured to deliver a second chemical compositionaccording to the second digital data, Dig2, The two combined merge andrepresent the image of the third digital data, Dig3. At least one of thechemical compositions includes a medicament while the other can be apolymer gel, hydrogel, brush polymer, another medicament or combinationsthereof.

Referring to FIG. 6, it illustrates an embodiment of thecomputer-implemented system for producing an oral appliance. An inputdevice or scanner 60 is used to scan the oral cavity of and thusgenerate a digital record of the patient's mouth (BI). The scanner canbe an MRI scanner, a CT scanner, a PET scanner, a digital scanner, anX-Ray machine, or an intra-oral scanner, for example. In variousembodiments, scanner 60 can scan the patient's teeth, soft tissue, orboth to obtain a digital data set of the teeth and/or soft tissue areasinside the mouth from which is generated the Base Image. The digitaldata can be stored in a database, such as for example a computer thathas a processor 62, which sends the digital data to its memory 64 and/orcan display it in a virtual 3D image display 66 of processor 62. Thedatabase and/or processor can comprise an input device (e.g., keyboard,touch screen, voice activation, etc.) to allow a user to enter, display,edit, and/or transmit on or more images from Dig1, Dig2, Dig3. Theprocessor 62 comprises logic to execute one or more instructions tocarry instructions of the computer system (e.g., transmit instructionsto the 3D printer, etc.). The logic for executing instructions may beencoded in one or more tangible media for execution by the processor 62.For example, the processor 62 may execute codes stored in acomputer-readable medium such as memory 64. The computer-readable mediummay be, for example, electronic (e.g., RAM (random access memory), ROM(read-only memory), EPROM (erasable programmable read-only memory)),magnetic, optical (e.g., CD (compact disc), DVD (digital video disc)),electromagnetic, semiconductor technology, or any other suitable medium.

Based on memory 64, processor 62 can generate Dig2 and Dig3 andthereafter send a 3D image to the 3D printer 68 of a stereolithographyapparatus.

In various embodiments, an authorized user can input, edit data andapprove or prescribe a treatment plan based on the virtual 3D imagesdisplayed at the user interface of the computer processor 62 and/oranother treating computer networked with computer processor 62. Althoughthe components of the system of FIG. 6 are shown as separate, they maycombined in one or more computer systems. Indeed, they may be one ormore hardware, software, or hybrid components residing in (ordistributed among) one or more local or remote computer systems. It alsoshould be readily apparent that the components of the system asdescribed herein may be merely logical constructs or routines that areimplemented as physical components combined or further separated into avariety of different components, sharing different resources (includingprocessing units, memory, clock devices, software routines, logiccommands, etc.) as required for the particular implementation of theembodiments disclosed. Indeed, even a single general purpose computer(or other processor-controlled device) executing a program stored on anarticle of manufacture (e.g., recording medium or other memory units) toproduce the functionality referred to herein may be utilized toimplement the illustrated embodiments. It also will be understood thatthe a plurality of computers or servers can be used to allow the systemto be a network based system having a plurality of computers linked toeach other over the network or Internet or the plurality of computerscan be connected to each other to transmit, edit, and receive data viacloud computers.

The computer (e.g., memory, processor, storage component, etc.) may beaccessed by authorized users. Authorized users may include at least onedentist or dental specialist, dental hygienist, oral surgeon, physician,surgeon, nurse, patient, and/or health care provider, manufacturer,etc.).

The user can interface with the computer via a user interface that mayinclude one or more display devices (e.g., CRT, LCD, or other knowndisplays) or other output devices (e.g., printer, etc.), and one or moreinput devices (e.g., keyboard, mouse, stylus, touch screen interface, orother known input mechanisms) for facilitating interaction of a userwith the system via user interface. The user interface may be directlycoupled to database or directly coupled to a network server system viathe Internet or cloud computing. In accordance with one embodiment, oneor more user interfaces are provided as part of (or in conjunction with)the illustrated systems to permit users to interact with the systems.

The user interface device may be implemented as a graphical userinterface (GUI) containing a display or the like, or may be a link toother user input/output devices known in the art. Individual ones of aplurality of devices (e.g., network/stand-alone computers, personaldigital assistants (PDAs), WebTV (or other Internet-only) terminals,set-top boxes, cellular/phones, screenphones, pagers, blackberry, smartphones, iPhone, iPad, table, peer/non-peer technologies, kiosks, orother known (wired or wireless) communication devices, etc.) maysimilarly be used to execute one or more computer programs (e.g.,universal Internet browser programs, dedicated interface programs, etc.)to allow users to interface with the systems in the manner described.Database hardware and software can be developed for access by usersthrough personal computers, mainframes, and other processor-baseddevices. Users may access and data stored locally on hard drives,CD-ROMs, stored on network storage devices through a local area network,or stored on remote database systems through one or more disparatenetwork paths (e.g., the Internet).

The database can be stored in storage devices or systems (e.g., RandomAccess Memory (RAM), Read Only Memory (ROM), hard disk drive (HDD),floppy drive, zip drive, compact disk-ROM, DVD, bubble memory, flashdrive, redundant array of independent disks (RAID), network accessiblestorage (NAS) systems, storage area network (SAN) systems, etc.), CAS(content addressed storage) may also be one or more memory devicesembedded within a CPU, or shared with one or more of the othercomponents, and may be deployed locally or remotely relative to one ormore components interacting with the memory or one or more modules. Thedatabase may include data storage device, a collection component forcollecting information from users or other computers into centralizeddatabase, a tracking component for tracking information received andentered, a search component to search information in the database orother databases, a receiving component to receive a specific query froma user interface, and an accessing component to access centralizeddatabase. Receiving component is programmed for receiving a specificquery from one of a plurality of users. The database may also include aprocessing component for searching and processing received queriesagainst data storage device containing a variety of informationcollected by collection device.

The disclosed system may, in some embodiments, be a computer networkbased system. The computer network may take any wired/wireless form ofknown connective technology (e.g., corporate or individual LAN,enterprise WAN, intranet, Internet, Virtual Private Network (VPN),combinations of network systems, etc.) to allow a server to providelocal/remote information and control data to/from other locations (e.g.,other remote database servers, remote databases, network servers/userinterfaces, etc.). In accordance with one embodiment, a network servermay be serving one or more users over a collection of remote anddisparate networks (e.g., Internet, intranet, VPN, cable, specialhigh-speed ISDN lines, etc.). The network may comprise one or moreinterfaces (e.g., cards, adapters, ports) for receiving data,transmitting data to other network devices, and forwarding received datato internal components of the system (e.g., 3D printers, printer heads,etc.).

In accordance with one embodiment of the present application, the datamay be downloaded in one or more textual/graphical formats (e.g., RTF,PDF, TIFF, JPEG, STL, XML, XDFL, TXT etc.), or set for alternativedelivery to one or more specified locations (e.g., via e-mail, fax,regular mail, courier, etc.) in any desired format (e.g., print, storageon electronic media and/or computer readable storage media such asCD-ROM, etc.). The user may view viewing the search results andunderlying documents at the user interface, which allows viewing of oneor more documents on the same display.

In various embodiments, the computer software can create a 2D or 3Ddigital image of the patient's oral cavity to allow the treatmentprovider to review and discuss the proposed treatment with the patient.In another embodiment, the software can process the scanned data andprovide the user/operator with useful data including tooth measurements(e.g. arch width, arch length, tooth size, angulations, sulcus size,etc.) to assist the user in fine-tuning the treatment plan. The computercan then provide the operator with options in staging the treatment planfrom one stage to another stage, or it can completely generate allstages ranging from the initial to final desired stage. The staging canbe done automatically.

FIG. 7 is a flow chart illustrating the logic steps followed byprocessor 62. The first step 70 comprises generating a Base Image (BI)of at least a portion of the teeth and/or soft tissues by using animaging device. In step 72, the BI is stored in the memory of theprocessor. In step 74, a first data set (Dig1) is generated by thecomputer additively layering over the BT of at least a portion of theteeth and/or soft tissues. The Dig1 is stored.

In step 76, a second data set (Dig2) is generated by digitallysegmenting at least a portion of the teeth and/or soft tissues from theBase Image.

Thereafter, in step 78, the processor can decide if all discrete regionsof the oral cavity in need of treatment have been identified or if theyhave not been, then the digital segmentation step will occur again. Dig2will also be checked for accuracy.

If all the desired discrete regions have been identified, then in step80, the processor stores the data, which includes the discrete regionsin need of treatment as a separate set corresponding to Dig2. The firstand second data sets are combined in step 82 to generate a third dataset corresponding to Dig3. The third data set is stored in step 84 andthen sent to a 3D printer in step 86.

FIG. 8 is a flow chart illustrating an embodiment of thecomputer-implemented system for treating a patient utilizing an oralappliance produced according to this disclosure. As described above, theoral cavity of the patient is scanned and a mold may be generated instep 90. Based on the information gathered in step 90, Dig1 isgenerated. Subsequently, a second digital data set is generated viadigital segmentation and Dig2 is obtained in step 94. As discussedabove, Dig1 and Dig2 digital data sets are combined in step 96 togenerate Dig3, which provides the logic and instructions to a 3D printerto print Dig3 in step 98. The oral appliances produced by astereolithography are then rinsed and loaded with medicaments in step100. The oral appliances are then dried and packed in step 102 andshipped to a dental professional in step 104. Alternatively, there maybe no rinse step or medicament loading as the stereolithography machinemay have the medicaments already loaded in its print head. In step 106,the patient receives the oral appliances and inserts them as required ina daily process in step 108. After the treatment period of step 110 iscompleted, each oral appliance is removed and discarded in step 112.Alternatively, if a diagnosis needs to be made the oral appliances canbe sent to a laboratory for testing and then the oral appliancesdisposed of by the laboratory.

Stereolithography

Stereolithography is the manufacturing process that may be employed forrapidly and accurately producing the oral appliances described herein. Acommercially-available stereolithography apparatus (SLA) may be employedto carry out the rapid prototyping methods described herein. In manycases, stereolithography is carried out using a defined amount of liquidUV-curable photopolymer, which can be a “resin” and an ultraviolet (UV)laser to assemble all or a portion of the oral appliance one layer at atime. According to such methods, the laser beam will “trace” across-sectional pattern, for each layer of the oral appliance, on thesurface of the liquid resin. By exposing the resin to UV energy, theresin solidifies (or “cures”) in accordance with the pattern traced bythe beam of energy, which adheres to the layer beneath it.

After a pattern has been traced by the beam of UV energy, a so-calledelevator platform within the SLA descends by a single layer thickness,typically about 0.05 mm to 0.15. Next, a resin-filled blade traversesacross each part of the cross-section, which re-coats the model with newUV-curable resin. On this new layer of resin, the subsequent layerpattern is traced, adhering to the previous layer. This process allowsfor a complete three-dimensional, real-sized prototyped oral applianceto be produced. After a prototype oral appliance is produced, the oralappliance may, optionally, be cleaned and the excess resin removedtherefrom by immersion in a chemical bath and then cured in a UV oven.U.S. Pat. No. 4,575,330 (“Apparatus for Production of Three-DimensionalObjects by Stereolithography”) provides a non-limiting method ofstereolithography, which may be used in the present application and ishereby incorporated by reference in its entirety. With respect to theoral appliance described herein, the print heads of the SLA can dispensepolymers according to instructions provided by Dig1 and Dig2 to generateDig3 as described above. Accordingly, the viscosity of the polymer,curing rates, feed rates to the print heads can be considered inmanufacturing the oral appliances described herein.

An alternate method of stereolithography involves the deposition ofsuccessive layers of liquid or powder onto a hard surface, with eachlayer immediately cured by a beam of UV energy, and in this way buildsup the oral appliance from a series of cross sectional patterns of Dig3.These layers, which correspond to the virtual cross section of Dig3, arejoined together or fused automatically to create the oral appliance.Further, it will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

1-15. (canceled)
 16. A computer implemented method of making an oralappliance, the method comprising: creating a digital record of apatient's oral cavity by obtaining a baseline digital image of at leasta portion of the patient's teeth, and/or soft tissue of the patient'soral cavity; obtaining a first digital image (Dig1) of an oral appliancecorresponding to the at least a portion of the patient's teeth, and/orsoft tissue of the patient's oral cavity of the baseline image, creatinga second digital image (Dig2) corresponding to at least a portion of thepatient's teeth and/or soft tissue of the patient's oral cavity in needof treatment; combining the first digital image and the second digitalimage to form a third digital image (Dig3) of the oral appliance thatcomprises the treatment area and storing the third digital image in thecomputer. 17-37. (canceled)
 38. A computer implemented method of claim16 wherein, creating a digital record of the patient's oral cavity byobtaining a baseline digital image of at least a portion of thepatient's teeth, and/or soft tissue of the patient's oral cavitycomprises: taking an impression of the patient's oral cavity using suchmaterials as alginate, polyvinals, silicones or a combination thereof.39. A computer implemented method of claim 16 wherein obtaining abaseline digital image of at least a portion of the patient's teeth,and/or soft tissue of the patient's oral cavity further comprisesdigitally storing a permanent record of the topography of least aportion of the patient's teeth, and/or soft tissue of the patient's oralcavity for future iterations of oral appliances.
 40. A computerimplemented method of claim 16 wherein obtaining the first digital image(Dig1) comprises an additive process wherein programmatically theplatform appliance image is digitally layered over the baseline digitalimage.
 41. A computer implemented method of claim 16 wherein the digitalimage (Dig1) is a platform carrier for delivering medicaments and/orcells to at least a portion of the patient's teeth, and/or soft tissueof the patient's oral cavity.
 42. A computer implemented method of claim16 wherein obtaining the second digital image (Dig2) comprises asubtractive process of the baseline image made through programmanipulations to treat at least a portion of the patient's teeth and/orsoft tissue of the patient's oral cavity in need of treatment.
 43. Acomputer implemented method of claim 16, the method further comprising:using the third digital image (Dig3) to print the oral appliancevirtually made through the computer.
 44. A computer implemented methodof claim 16, wherein the thickness of surface oral appliance isincrementally configured for treatment of a gum disease.
 45. A computerimplemented method of claim 16, wherein the oral appliance is in oralappliance form and comprises at least two oral appliances.
 46. Acomputer implemented method of claim 16, wherein the oral appliancecomprises tissue for grafting a cleft palate or other defects of thejaws and face.
 47. A computer implemented method of claim 16, whereinthe oral appliance is monolithic and an interior surface is custom fitto contours of the teeth and/or soft tissue areas inside the oral cavityof the patient in need of treatment.
 48. A computer implemented methodof claim 16, further comprising storing a three-dimensionalrepresentation of the third digital image (Dig3) in format suitable foruse by a manufacturer to manufacture the oral appliance.
 49. A computerimplemented method of claim 16, wherein creating a digital record of thepatient's oral cavity comprises imaging devices including at least oneof a digital camera, X-ray device, hand-held 3-D scanner, laser scanner,computed tomography (CT) scanner, magnetic resonance imaging (MRI)scanner, coordinate measuring machine, destructive scanner or ultrasoundscanner.